Heteroaryl antagonists of prostaglandin d2 receptors

ABSTRACT

Described herein are heteroaryl compounds that are antagonists of PGD2 receptors. Also described are pharmaceutical compositions and medicaments that include the heteroaryl compounds described. Also described herein are methods of using such antagonists of PGD2 receptors, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other PGD2-dependent or PGD2-mediated conditions or diseases.

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patentapplication No. 61/101,964 entitled “HETEROARYL ANTAGONISTS OFPROSTAGLANDIN D₂ RECEPTORS” filed on Oct. 1, 2008, which is incorporatedby reference in its entirety.

FIELD OF THE INVENTION

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments comprising such compounds,and methods of using such compounds to treat, prevent or diagnosediseases, disorders or conditions associated with prostaglandin D₂.

BACKGROUND OF THE INVENTION

Prostaglandins are acidic lipids derived from the metabolism ofarachidonic acid by the action of cyclooxygenase enzymes and downstreamsynthases. Prostaglandins have a diverse range of activities and have awell recognized role in pain and inflammation. Prostaglandin D₂ (PGD₂)is an acidic lipid mediator derived from the metabolism of arachidonicacid by cyclooxygenases and PGD₂ synthases. PGD₂ is produced by mastcells, macrophages and Th2 lymphocytes in response to local tissuedamage as well as allergic inflammation in diseases such as asthma,rhinitis, and atopic dermatitis. Exogenous PGD₂ applied to bronchialairways elucidates many characteristics of an asthmatic responsesuggesting that PGD₂ plays an important pro-inflammatory role inallergic diseases.

PGD₂ binds to a number of receptors, which include the thromboxane-typeprostanoid (TP) receptor, PGD₂ receptor (DP, also known as DP₁) andchemoattractant receptor-homologous molecule expressed on Th2 cells(CRTH2; also known as DP₂). DP₂ is associated with promoting chemotaxisand activation of Th2 lymphocytes, eosinophils and basophils. Inparticular, PGD₂ binds to DP₂, and mediates its effects through aG_(i)-dependant elevation in calcium levels and reduction ofintracellular cyclic AMP. In Th2 lymphocytes, IL4, IL5 and IL13 cytokineproduction is stimulated. These cytokines have been implicated innumerous biological actions including, by way of example only,immunoglobulin E production, airway response, mucous secretion, andeosinophil recruitment.

SUMMARY OF THE INVENTION

Presented herein are compounds, pharmaceutical compositions andmedicaments, methods, for (a) diagnosing, preventing, or treatingallergic and non-allergic inflammation, (b) mitigating adverse signs andsymptoms that are associated with inflammation, and/or (c) controllingimmunological, or proliferative disorders. These disorders may arisefrom one or more of a genetic, iatrogenic, immunological, infectious,oncological, toxic, surgical, and/or traumatic etiology. In one aspect,the methods, compounds, pharmaceutical compositions, and medicamentsdescribed herein comprise antagonists of PGD₂ receptors. In one aspect,the methods, compounds, pharmaceutical compositions, and medicamentsdescribed herein comprise antagonists of DP₂

In one aspect provided herein are compounds of Formula (I), Formula(II), Formula (III), Formula (IV) and Formula (V), pharmaceuticallyacceptable salts, pharmaceutically acceptable prodrugs, N-oxides,metabolites, and pharmaceutically acceptable solvates thereof, which areanatgonists of DP₂, and are used to treat patients suffering from one ormore PGD₂-dependent conditions or diseases, including, but not limitedto, asthma, rhinitis, chronic obstructive pulmonary disease, pulmonaryhypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis,inflammatory bowel disease, adult respiratory distress syndrome,myocardial infarction, aneurysm, stroke, cancer, wound healing,endotoxic shock, pain, proliferative disorders, inflammatory conditions,eosinophilic esophagitis, eosinophil-associated gastrointestinaldisorders (EGID), idiopathic hypereosinophilic syndrome, otitis, airwayconstriction, mucus secretion, nasal congestion, increased microvascularpermeability and recruitment of eosinophils, urticaria, sinusitis,angioedema, anaphylaxia, chronic cough and Churg Strauss syndrome. Insome embodiments, PGD₂-dependent conditions or diseases include thosewherein an absolute or relative excess of PGD₂ is present and/orobserved.

In one aspect is a compound having the structure of Formula (I),pharmaceutically acceptable salts, pharmaceutically acceptable solvates,N-oxides, or pharmaceutically acceptable prodrugs thereof:

wherein,

-   -   ring B is a substituted or unsubstituted heteroaryl, wherein if        ring B is substituted, then each substituent on ring B is        independently selected from H and R^(B);    -   X is a bond, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR¹³—, —CH₂—, or        —C(═O)—;    -   Q is —C(═O)-Q¹, tertrazolyl, or a carboxylic acid bioisostere;        -   Q¹ is —OH, —OR¹⁵, —NHSO₂R⁹, —N(R¹⁰)₂, —NH—OH, or —NH—CN;    -   each R¹ is independently selected from H, F, —CH₃ and —CH₂CH₃;    -   each of R², R³, R⁴, R⁵ and R^(B) is independently selected from        H, halogen, —CN, —NO₂, —OH, —OR¹⁰, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹,        —N(R¹⁰)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰,        —OCO₂R¹⁰, —N(R¹⁰)₂, —NHCH₂CO₂R¹⁰, —OCH₂CO₂R¹⁰, —SCH₂CO₂R¹⁰,        —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NR¹⁰C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹,        —NR¹⁰—C₁-C₄alkyl-C(═O)R⁹, —NR¹⁰C(═O)OR⁹, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy,        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;    -   each R⁶ is H;    -   R⁷ is —C(═O)R¹¹, —C(═O)OR¹², —C(═O)N(R¹³)₂, —S(═O)₂N(R¹³)₂ or        —S(═O)₂R¹²;        -   R¹¹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a            substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted            or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted            heteroaryl, —C₁-C₄alkyl-(substituted or unsubstituted            C₃-C₁₀cycloalkyl), —C₁-C₄alkyl-(substituted or unsubstituted            C₂-C₁₀heterocycloalkyl), —C₁-C₄alkyl-(substituted or            unsubstituted aryl) or —C₁-C₄alkyl-(substituted or            unsubstituted heteroaryl); or        -   R¹¹ is L³-X³-Q³;            -   L³ is a C₁-C₆alkylene;            -   X³ is a bond, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR¹³—;            -   Q³ is a C₁-C₆alkyl, C₁-C₆fluoroalkyl a substituted or                unsubstituted C₃-C₁₀cycloalkyl, a substituted or                unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or                unsubstituted aryl, a substituted or unsubstituted                heteroaryl, —C₁-C₄alkyl-(substituted or unsubstituted                C₃-C₁₀cycloalkyl), —C₁-C₄alkyl-(substituted or                unsubstituted heterocycloalkyl),                —C₁-C₄alkyl-(substituted or unsubstituted aryl), or                C₁-C₄alkyl-(substituted or unsubstituted heteroaryl);        -   R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a            substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted            or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted            heteroaryl, —C₁-C₄alkyl-(substituted or unsubstituted            C₃-C₁₀cycloalkyl), —C₁-C₄alkyl-(substituted or unsubstituted            C₂-C₁₀heterocycloalkyl), —C₁-C₄alkyl-(substituted or            unsubstituted aryl) or —C₁-C₄alkyl-(substituted or            unsubstituted heteroaryl);        -   each R¹³ is independently H, —CN, C₁-C₆alkyl,            C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or            unsubstituted C₃-C₁₀cycloalkyl, a substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, substituted or unsubstituted heteroaryl,            —C₁-C₄alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),            —C₁-C₄alkyl-(substituted or unsubstituted            C₂-C₁₀heterocycloalkyl), —C₁-C₄alkyl-(substituted or            unsubstituted aryl) or —C₁-C₄alkyl-(substituted or            unsubstituted heteroaryl); or        -   two R¹³ groups attached to the same N atom are taken            together with the N atom to which they are attached to form            a substituted or unsubstituted heterocycle;    -   R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, (a        substituted or unsubstituted monocyclic or bicyclic        C₃-C₁₀cycloalkyl), (a substituted or unsubstituted monocyclic or        bicyclic C₃-C₁₀heterocycloalkyl), a substituted or unsubstituted        aryl, or a substituted or unsubstituted heteroaryl,        C₁-C₄alkylene-R¹⁴, —C₁-C₄alkylene-O—R¹⁴, —C₁-C₄alkylene-S—R¹⁴,        —C₁-C₄alkylene-S(═O)—R¹⁴, —C₁-C₄alkylene-S(═O)₂—R¹⁴,        —C₁-C₄alkylene-N(R¹⁴)₂, —C₁-C₄alkylene-C(═O)—R¹⁴,        —C₁-C₄alkylene-C(═O)O—R¹⁴—, —C₁-C₄alkylene-OC(═O)—R¹⁴,        —C₁-C₄alkylene-NR¹⁴C(═O)—R¹⁴ or —C₁-C₄alkylene-C(═O)N(R¹⁴)₂;        -   each R¹⁴ is independently selected from H, C₁-C₆alkyl,            C₁-C₆heteroalkyl, C₁-C₆haloalkyl, a substituted or            unsubstituted C₃-C₁₀cycloalkyl, a substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted benzyl,            or a substituted or unsubstituted heteroaryl;    -   R⁹ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a        substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or        unsubstituted aryl, a substituted or unsubstituted benzyl, a        substituted or unsubstituted heteroaryl,        —C₁-C₄alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkyl-(substituted or        unsubstituted aryl), or —C₁-C₄alkyl-(substituted or        unsubstituted heteroaryl);    -   each R¹⁰ is independently selected from H, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a substituted or        unsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted benzyl, a substituted or        unsubstituted heteroaryl, —C₁-C₄alkyl-(substituted or        unsubstituted C₃-C₁₀cycloalkyl), —C₁-C₄alkyl-(substituted or        unsubstituted C₂-C₁₀heterocycloalkyl), —C₁-C₄alkyl-(substituted        or unsubstituted aryl), and —C₁-C₄alkyl-(substituted or        unsubstituted heteroaryl); or    -   two R¹⁰ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted heterocycloalkyl; and    -   each R¹⁵ is independently selected from H and C₁-C₆alkyl.

For any and all of the embodiments, substituents can be selected fromamong from a subset of the listed alternatives.

In some embodiments, X is a bond, —O—, or —CH₂—. In other embodiments, Xis a bond. In other embodiments, X is —O—. In some other embodiments, Xis —CH₂—.

In some embodiments, ring B is a substituted or unsubstituted monocyclicheteroaryl ring or a substituted or unsubstituted bicyclic heteroarylring, where ring B contains 0-1 oxygen atoms; 0-1 sulfur atoms; and 0-4nitrogen atoms, wherein if ring B is substituted, then each substituenton ring B is independently selected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstituted heteroarylring selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl,imidazolyl, pyrazolyl, isothiazolyl, triazolyl, tetrazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl,indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, azaindolyl,pyrazolopyridinyl, thiazolopyrimidinyl, thiazolopyridinyl,pyridothienyl, pyrimidiothienyl and pyrrolopyrimidinyl, wherein if ringB is substituted, then each substituent on ring B is independentlyselected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstituted monocyclicheteroaryl ring, where ring B contains 0-1 oxygen atoms; 0-1 sulfuratoms; and 1-3 nitrogen atoms, wherein if ring B is substituted, theneach substituent on ring B is independently selected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstituted heteroarylring selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl,pyrazolyl, isothiazolyl, triazolyl, and tetrazolyl, wherein if ring B issubstituted, then each substituent on ring B is independently selectedfrom H and R^(B).

In some embodiments, ring B is a substituted or unsubstituted 6-memberedmonocyclic heteroaryl ring, where ring B contains 1-3 nitrogen atoms,wherein if ring B is substituted, then each substituent on ring B isindependently selected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstituted 6-memberedmonocyclic heteroaryl ring, where ring B contains 1 or 2 nitrogen atoms,wherein if ring B is substituted, then each substituent on ring B isindependently selected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstituted heteroarylring selected from pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl,wherein if ring B is substituted, then each substituent on ring B isindependently selected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstituted pyridinyl,wherein if ring B is substituted, then ring B is substituted with 1 or 2R^(B).

In some embodiments, ring B is a substituted or unsubstitutedsubstituted or unsubstituted bicyclic heteroaryl ring, where ring Bcontains 0-1 oxygen atoms; 0-1 sulfur atoms; and 0-4 nitrogen atoms,wherein if ring B is substituted, then each substituent on ring B isindependently selected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstituted bicyclicheteroaryl selected from quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl,benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl,pyridopyrimidinyl, pyrazolopyrimidinyl, azaindolyl, pyrazolopyridinyl,thiazolopyrimidinyl, thiazolopyridinyl, pyridothienyl, pyrimidiothienyland pyrrolopyrimidinyl, wherein if ring B is substituted, then eachsubstituent on ring B is independently selected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstitutedsubstituted or unsubstituted bicyclic heteroaryl ring, where ring Bcontains 0-1 oxygen atoms; 0-1 sulfur atoms; and 1-4 nitrogen atoms,wherein if ring B is substituted, then each substituent on ring B isindependently selected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstitutedquinolinyl, wherein if ring B is substituted, then ring B is substitutedwith 1 or 2 R^(B).

In some embodiments, the groups

are on adjacent atoms of ring B.

In some embodiments, the groups

are on adjacent carbon atoms of ring B.

In some embodiments, if ring B is substituted, then ring B issubstituted with 1 or 2 R^(B).

In some embodiments, if ring B is substituted, then ring B issubstituted with R^(B).

In some embodiments, Q is —C(═O)-Q¹. In some embodiments, Q is—C(═O)—OH.

In some embodiments, Q is —C(═O)-Q¹; Q¹ is —OH or —OR¹⁵; each R¹ isindependently selected from H, F, and —CH₃; R⁷ is —C(═O)R¹¹, —C(═O)OR¹²,or —C(═O)N(R¹³)₂; R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, (asubstituted or unsubstituted monocyclic or bicyclic C₃-C₁₀cycloalkyl),(a substituted or unsubstituted monocyclic or bicyclicC₂-C₁₀heterocycloalkyl), a substituted or unsubstituted aryl, or asubstituted or unsubstituted heteroaryl, C₁-C₆alkylene-R¹⁴,—C₁-C₆alkylene-O—R¹⁴, —C₁-C₆alkylene-NR¹⁰—R¹⁴, —C₁-C₆alkylene-C(═O)—R¹⁴;—C₁-C₆alkylene-C(═O)O—R¹⁴—, or —C₁-C₆alkylene-C(═O)NR¹⁰—R¹⁴; each R¹⁴ isindependently selected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, a substituted or unsubstituted cycloalkyl, a substitutedor unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl,a substituted or unsubstituted benzyl, or a substituted or unsubstitutedheteroaryl.

In some embodiments , Q¹ is —OH, —OCH₃, or —OCH₂CH₃; each R¹ is H.

In some embodiments, Q¹ is —OH; each of R², R³, and R⁴ is eachindependently H, halogen, —CN, —OH, —OR¹⁰, C₁-C₄alkyl, C₁-C₄fluoroalkyl,C₁-C₄fluoroalkoxy, C₁-C₄alkoxy, or C₁-C₄heteroalkyl; R⁵ is H.

In some embodiments, R¹¹ is C₁-C₄alkyl, C₃-C₆cycloalkyl, a substitutedor unsubstituted phenyl, a substituted or unsubstituted monocyclicheteroaryl, —C₁-C₂alkyl-(substituted or unsubstituted phenyl) or—C₁-C₂alkyl-(substituted or unsubstituted monocyclic heteroaryl); or R¹¹is L³-X³-Q³; L³ is a C₁-C₄alkylene; X³ is a bond, or —O—; Q³ is aC₁-C₆alkyl, substituted or unsubstituted phenyl, or—C₁-C₄alkyl-(substituted or unsubstituted phenyl); R¹² is C₁-C₆alkyl,C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, a substituted orunsubstituted monocyclic heteroaryl, —C₁-C₂alkyl-(substituted orunsubstituted phenyl) or —C₁-C₂alkyl-(substituted or unsubstitutedmonocyclic heteroaryl); each R¹³ is independently H, C₁-C₆alkyl,C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, substituted orunsubstituted monocyclic heteroaryl, —C₁-C₂alkyl-(substituted orunsubstituted phenyl) or —C₁-C₂alkyl-(substituted or unsubstitutedmonocyclicheteroaryl).

In some embodiments, each R^(B) is independently selected from H,halogen, —CN, —OH, —OR¹⁰, —S(═O)₂R⁹, —NHS(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,—CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NHC(═O)N(R¹⁰)₂, —NHC(═O)R⁹,—NHC(═O)OR⁹, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy,C₁-C₄alkoxy, C₁-C₄heteroalkyl, a substituted or unsubstitutedC₃-C₆cycloalkyl, a substituted or unsubstituted C₂-C₆heterocycloalkyl, asubstituted or unsubstituted phenyl, and a substituted or unsubstitutedmonocyclic heteroaryl.

In some embodiments, R⁸ is C₁-C₆alkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, or a substituted or unsubstituted monocyclicheteroaryl, or —C₁-C₄alkylene-R¹⁴; R¹⁴ is —C₃-C₆cycloalkyl, asubstituted or unsubstituted phenyl, or a substituted or unsubstitutedmonocyclic heteroaryl.

In some embodiments, R¹¹ is C₁-C₄alkyl, C₃-C₆cycloalkyl,—C₁-C₂alkyl-(substituted or unsubstituted phenyl) or—C₁-C₂alkyl-(substituted or unsubstituted monocyclic heteroaryl); or R¹¹is L³-X³-Q³; L³ is a C₁-C₄alkylene; X³ is a bond, or —O—; Q³ is aC₁-C₆alkyl, substituted or unsubstituted phenyl, or—C₁-C₄alkyl-(substituted or unsubstituted phenyl); R¹² is C₁-C₆alkyl,—C₁-C₂alkyl-(substituted or unsubstituted phenyl) or—C₁-C₂alkyl-(substituted or unsubstituted monocyclic heteroaryl); eachR¹³ is independently H, C₁-C₆alkyl, —C₁-C₂alkyl-(substituted orunsubstituted phenyl) or —C₁-C₂alkyl-(substituted or unsubstitutedmonocyclicheteroaryl).

In some embodiments, R⁸ is C₁-C₄alkyl, C₃-C₆cycloalkyl, or—C₁-C₂alkylene-R¹⁴;

R¹⁴ is C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, or asubstituted or unsubstituted monocyclic heteroaryl.

In some embodiments, ring B is a substituted or unsubstituted pyridinyl,wherein if ring B is substituted, then ring B is substituted with 1 or 2R^(B).

In some embodiments, each R^(B) is independently selected from H,halogen, —CN, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy,C₁-C₄alkoxy, C₁-C₄heteroalkyl.

In some embodiments, ring B is a substituted or unsubstituted pyridinyl,wherein if ring B is substituted, then ring B is substituted with R^(B).

In some embodiments, R² is —C(═O)R¹¹.

In some embodiments, R² is —C(═O)OR¹².

In some embodiments, R² is —C(═O)N(R¹³)₂.

In some embodiments, one R¹³ is H, or C₁-C₄alkyl, and the other R¹³ isC₁-C₆alkyl, —C₁-C₂alkyl-(substituted or unsubstituted phenyl) or—C₁-C₂alkyl-(substituted or unsubstituted monocyclic heteroaryl).

In some embodiments, ring B is a substituted or unsubstitutedquinolinyl, wherein if ring B is substituted, then ring B is substitutedwith 1 or 2 R^(B); each R^(B) is independently selected from H, halogen,—CN, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, C₁-C₄alkoxy,C₁-C₄heteroalkyl.

In some embodiments, the compound of Formula (I) has the structure ofFormula (II):

wherein:each of A¹, A², A³, and A⁴ is each independently selected from C(R^(B)),N and —N⁺(—O⁻)—, provided that one or two of A¹, A², A³, and A⁴ is N or—N⁺(—O⁻)—.

In some embodiments, A² is CR^(B); A³ is CR^(B).

In some embodiments, A¹ is N or —N⁺(—O⁻)—.

In some embodiments, A⁴ is N or —N⁺(—O⁻)—.

In some embodiments, A² is CH; A³ is CR^(B).

In some embodiments, each R¹ is H; each of R², R³, and R⁴ is eachindependently H, halogen, —CN, —OH, —OR¹⁰, C₁-C₄alkyl, C₁-C₄fluoroalkyl,C₁-C₄fluoroalkoxy, C₁-C₄alkoxy, or C₁-C₄heteroalkyl; each R^(B) isindependently selected from H, halogen, —CN, —NO₂, —OH, —OR¹⁰, —SR⁹,—S(═O)R⁹, —S(═O)₂R⁹, —N(R¹⁰)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,—OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂,—NR¹⁰C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹, —NR¹⁰—C₁-C₄alkyl-C(═O)R⁹,—NR¹⁰C(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,C₁-C₆alkoxy, C₁-C₆heteroalkyl, a substituted or unsubstitutedC₃-C₆cycloalkyl, a substituted or unsubstituted C₂-C₆heterocycloalkyl, asubstituted or unsubstituted phenyl, and a substituted or unsubstitutedheteroaryl; R¹⁵ is H, —CH₃, or —CH₂CH₃.

In some embodiments, A¹ is N, —N⁺(—O⁻)— or CH; A² is CH; A³ is CR^(B);and A⁴ is N, —N⁺(—O⁻)— or CH; provided that at least one of A¹ and A⁴ isN or —N⁺(—O⁻)—.

In some embodiments, each R^(B) is independently selected from H,halogen, —CN, —NO₂, —OH, —OR¹⁰, —S(═O)₂R⁹, —NHS(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,—C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰, N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,—OC(═O)N(R¹⁰)₂, —NHC(═O)N(R¹⁰)₂, —NHC(═O)R⁹, —NH—C₁-C₄alkyl-C(═O)R⁹,—NHC(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,C₁-C₆alkoxy, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted C₂-C₆heterocycloalkyl, a substituted or unsubstitutedphenyl, and a substituted or unsubstituted heteroaryl.

In some embodiments, X is a bond; each R^(B) is independently selectedfrom H, halogen, —CN, —NO₂, —OH, —OR¹⁰, —S(═O)₂R⁹, —NHS(═O)₂R⁹,—S(═O)₂N(R¹⁰)₂, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NHC(═O)N(R¹⁰)₂,—NHC(═O)R⁹, —NH—C₁-C₄alkyl-C(═O)R⁹, —NHC(═O)OR⁹, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl,C₃-C₆cycloalkyl, a substituted or unsubstituted C₂-C₆heterocycloalkyl, asubstituted or unsubstituted phenyl, and a substituted or unsubstitutedmonocyclic heteroaryl.

In some embodiments, the compound of Formula (II) has the followingstructure of Formula (IV):

In some embodiments, R⁷ is —C(═O)R¹¹, —C(═O)OR¹², or —C(═O)N(R¹³)₂; R⁸is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, (a substituted orunsubstituted monocyclic or bicyclic C₃-C₁₀cycloalkyl), (a substitutedor unsubstituted monocyclic or bicyclic C₂-C₁₀heterocycloalkyl), asubstituted or unsubstituted aryl, or a substituted or unsubstitutedheteroaryl, C₁-C₆alkylene-R¹⁴, —C₁-C₆alkylene-O—R¹⁴,—C₁-C₆alkylene-NR¹⁰—R¹⁴, —C₁-C₆alkylene-C(═O)—R¹⁴,C₁-C₆alkylene-C(═O)—R¹⁴—, or —C₁-C₆alkylene-C(═O)NR¹⁰—R¹⁴; each R¹⁴ isindependently selected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, a substituted or unsubstituted cycloalkyl, a substitutedor unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl,a substituted or unsubstituted benzyl, or a substituted or unsubstitutedheteroaryl.

In some embodiments, R¹¹ is C₁-C₄alkyl, C₃-C₆cycloalkyl, a substitutedor unsubstituted phenyl, a substituted or unsubstituted monocyclicheteroaryl, —C₁-C₂alkyl-(substituted or unsubstituted phenyl) or—C₁-C₂alkyl-(substituted or unsubstituted monocyclic heteroaryl); or R¹¹is L³-X³-Q³; L³ is a C₁-C₄alkylene; X³ is a bond, or —O—; Q³ is aC₁-C₆alkyl, substituted or unsubstituted phenyl, or—C₁-C₄alkyl-(substituted or unsubstituted phenyl); R¹² is C₁-C₆alkyl,C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, a substituted orunsubstituted monocyclic heteroaryl, —C₁-C₂alkyl-(substituted orunsubstituted phenyl) or —C₁-C₂alkyl-(substituted or unsubstitutedmonocyclic heteroaryl); each R¹³ is independently H, C₁-C₆alkyl,C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, substituted orunsubstituted monocyclic heteroaryl, —C₁-C₂alkyl-(substituted orunsubstituted phenyl) or —C₁-C₂alkyl-(substituted or unsubstitutedmonocyclicheteroaryl).

In some embodiments, R⁸ is C₁-C₆alkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, or a substituted or unsubstituted monocyclicheteroaryl, or —C₁-C₄alkylene-R¹⁴; R^(14 is C) ₃-C₆cycloalkyl, asubstituted or unsubstituted phenyl, or a substituted or unsubstitutedmonocyclic heteroaryl.

In some embodiments, R¹¹ is C₁-C₄alkyl, C₃-C₆cycloalkyl,—C₁-C₂alkyl-(substituted or unsubstituted phenyl) or—C₁-C₂alkyl-(substituted or unsubstituted monocyclic heteroaryl); or R¹¹is L³-X³-Q³; L³ is a C₁-C₄alkylene; X³ is a bond, or —O—; Q³ is aC₁-C₆alkyl, substituted or unsubstituted phenyl, or—C₁-C₄alkyl-(substituted or unsubstituted phenyl); R¹² is C₁-C₆alkyl,—C₁-C₂alkyl-(substituted or unsubstituted phenyl) or—C₁-C₂alkyl-(substituted or unsubstituted monocyclic heteroaryl); eachR¹³ is independently H, C₁-C₆alkyl, —C₁-C₂alkyl-(substituted orunsubstituted phenyl) or —C₁-C₂alkyl-(substituted or unsubstitutedmonocyclicheteroaryl).

In some embodiments, R⁸ is C₁-C₄alkyl, C₃-C₆cycloalkyl, or—C₁-C₂alkylene-R¹⁴;

R¹⁴ is C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, or asubstituted or unsubstituted monocyclic heteroaryl.

In some embodiments, each R^(B) is independently selected from H,halogen, —CN, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy,C₁-C₄alkoxy, C₁-C₄heteroalkyl.

In some embodiments, R⁷ is —C(═O)R¹¹.

In some embodiments, R⁷ is —C(═O)OR¹².

In some embodiments, R⁷ is —C(═O)N(R¹³)₂; one R¹³ is H, or C₁-C₄alkyl,and the other R¹³ is C₁-C₆alkyl, —C₁-C₂alkyl-(substituted orunsubstituted phenyl) or —C₁-C₂alkyl-(substituted or unsubstitutedmonocyclic heteroaryl).

In some embodiments, R⁸ is C₁-C₄alkyl, or C₃-C₆cycloalkyl.

In some embodiments, R⁸ is —C₁-C₂alkylene-R¹⁴; R¹⁴ is a substituted orunsubstituted phenyl, or a substituted or unsubstituted monocyclicheteroaryl.

In some embodiments, the compound of Formula (I) has the structure ofFormula (III):

wherein:

-   -   each of A⁵ and A⁶ is each independently selected from C—R^(B), N        and —N⁺(—O⁻)—, provided that at least one of A⁵ or A⁶ is N or        —N⁺(—O⁻)—.

In some embodiments, A⁵ is N or —N⁺(—O⁻)—.

In some embodiments, A⁶ is N or —N⁺(—O⁻)—.

In some embodiments, each R^(B) is independently selected from H,halogen, —CN, —NO₂, —OH, —OR¹⁰, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹,—N(R¹⁰)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰,—OCO₂R¹⁰,) —N(R¹⁰)₂, —NHCH₂CO₂R¹⁰, —OCH₂CO₂R¹⁰, —SCH₂CO₂R¹⁰,—C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NR¹⁰C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹,—NR¹⁰—C₁-C₄alkyl-C(═O)R⁹, —NR¹⁰C(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl.

In some embodiments, each R^(B) is independently selected from H,halogen, —CN, —NO₂, —OH, —OR¹⁰, —S(═O)₂R⁹, —NHS(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,—C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂,—NHC(═O)N(R¹⁰)₂, —NHC(═O)R⁹, —NHC(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl.

In some embodiments, each R^(B) is independently selected from H,halogen, —CN, —NO₂, —OH, —OR¹⁰, —N(R¹⁰)₂, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl.

In some embodiments, at least two R^(B) are H. In some embodiments, atleast three R^(B) are H. In some embodiments, at least four R^(B) are H.

In some embodiments, each R¹ is H; R¹⁵ is H.

In some embodiments, each of R², R³, and R⁴ is each independently H,halogen, —CN, —OH, —OR¹⁰, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, or C₁-C₆heteroalkyl.

In some embodiments, each of R², R³, and R⁴ is each independently H,halogen, CN, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy, orC₁-C₄-fluoroalkoxy. In some embodiments, one of R², R³, or R⁴ is H,halogen, CN, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy, orC₁-C₄-fluoroalkoxy and two of R², R³, or R⁴ is H.

In some embodiments, at least one of R², R³, and R⁴ is H. In someembodiments, at least two of R², R³, and R⁴ is H. In some embodiments,R² is H. In some embodiments, R³ is H.

In some embodiments, R⁴ is H, halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄-fluoroalkoxy, or C₁-C₄alkoxy. In someembodiments, R⁴ is H, F, Cl, Br, —CN, —OH, —CH₃, —CF₃, —OCF₃, —OCH₂CF₃,—OCH₃ and —OCH₂CH₃. In some embodiments, R⁴ is H, F, Cl, —CH₃, —CF₃,—OCF₃, and —OCH₃.

In some embodiments, the compound of Formula (III) has the followingstructure of Formula (V):

In some embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,(a substituted or unsubstituted monocyclic or bicyclic cycloalkyl), asubstituted or unsubstituted aryl, a substituted or unsubstitutedheteroaryl, C₁-C₆alkylene-R¹⁴, or —C₁-C₆alkylene-O—R¹⁴; each R¹⁴ isselected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, a substituted orunsubstituted benzyl, and a substituted or unsubstituted heteroaryl.

In some embodiments, R⁷ is —C(═O)R¹¹, —C(═O)OR¹², or —C(═O)N(R¹³)₂;

In some embodiments, R⁷ is —C(═O)R¹¹.

In some embodiments, R¹¹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstitutedphenyl, a substituted or unsubstituted monocyclic heteroaryl,—C₁-C₄alkyl-C₃-C₆cycloalkyl, —C₁-C₄alkyl-(substituted or unsubstitutedphenyl) or —C₁-C₆alkyl-(substituted or unsubstituted monocyclicheteroaryl).

In some embodiments, R¹¹ is a substituted or unsubstituted aryl, asubstituted or unsubstituted heteroaryl, —C₁-C₂alkyl-(substituted orunsubstituted phenyl) or —C₁-C₂alkyl-(substituted or unsubstitutedmonocyclic heteroaryl).

In some embodiments, R¹¹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, or C₃-C₆cycloalkyl.

In some embodiments, R¹¹ is C₁-C₆alkyl or C₃-C₆cycloalkyl. In someembodiments, R¹¹ is C₁-C₄alkyl. In some embodiments, R¹¹ isC₃-C₆cycloalkyl

In some embodiments, R⁷ is —C(═O)OR¹².

In some embodiments, R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstituted aryl,a substituted or unsubstituted heteroaryl, —C₁-C₆alkyl-(substituted orunsubstituted C₃-C₆cycloalkyl), —C₁-C₆alkyl-(substituted orunsubstituted aryl) or —C₁-C₆alkyl-(substituted or unsubstitutedheteroaryl).

In some embodiments, R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, —C₁-C₄alkyl-C₃-C₆cycloalkyl,—C₁-C₄alkyl-(substituted or unsubstituted phenyl) or—C₁-C₄alkyl-(substituted or unsubstituted monocyclic heteroaryl).

In some embodiments, R¹² is C₁-C₆alkyl, —C₁-C₂alkyl-(substituted orunsubstituted phenyl) or —C₁-C₂alkyl-(substituted or unsubstitutedmonocyclic heteroaryl). In some embodiments, R¹² is—C₁-C₂alkyl-(substituted or unsubstituted phenyl) or—C₁-C₂alkyl-(substituted or unsubstituted monocyclic heteroaryl). Insome embodiments, R¹² is —C₁-C₂alkyl-(substituted or unsubstitutedphenyl).

In some embodiments, R⁷ is —C(═O)N(R¹³)₂.

In some embodiments, each R¹³ is independently H, —CN, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or unsubstitutedC₃-C₁₀cycloalkyl, a substituted or unsubstituted aryl, a substituted orunsubstituted heteroaryl, —C₁-C₆alkyl-(substituted or unsubstitutedaryl) or —C₁-C₆alkyl-(substituted or unsubstituted heteroaryl); or twoR¹³ groups attached to the same N atom are taken together with the Natom to which they are attached to form a substituted or unsubstitutedheterocycloalkyl.

In some embodiments, each R¹³ is independently H, —CN, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, a substituted or unsubstituted monocyclicheteroaryl, —C₁-C₄alkyl-(substituted or unsubstituted phenyl) or—C₁-C₆alkyl-(substituted or unsubstituted monocyclic heteroaryl).

In some embodiments, one R¹³ is H, or C₁-C₄alkyl, and the other R¹³ isH, C₁-C₄alkyl, —C₁-C₂alkyl-(substituted or unsubstituted phenyl) or—C₁-C₂alkyl-(substituted or unsubstituted monocyclic heteroaryl). Insome embodiments, one R¹³ is H, or C₁-C₄alkyl, and the other R¹³ is—C₁-C₂alkyl-(substituted or unsubstituted phenyl) or—C₁-C₂alkyl-(substituted or unsubstituted monocyclic heteroaryl). Insome embodiments, one R¹³ is H, or C₁-C₄alkyl, and the other R¹³ is—C₁-C₂alkyl-(substituted or unsubstituted phenyl).

In some embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl,C₃-C₆cycloalkyl or C₁-C₄alkylene-R¹⁴; R¹⁴ is a substituted orunsubstituted phenyl, or a substituted or unsubstituted monocyclicheteroaryl.

In some embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆heteroalkyl.

In some embodiments, R⁸ is C₁-C₆alkyl, or C₁-C₆heteroalkyl.

In some embodiments, R⁸ is C₁-C₆alkyl.

In some embodiments, R⁸ is C₁-C₄alkylene-R¹⁴; R¹⁴ is a substituted orunsubstituted phenyl, or a substituted or unsubstituted monocyclicheteroaryl. In some embodiments, R⁸ is —C₁-C₄alkylene-R¹⁴. In someembodiments, R⁸ is —C₁-C₂alkylene-R¹⁴. In some embodiments, R¹⁴ is asubstituted or unsubstituted phenyl.

Any combination of the groups described above for the various variablesis contemplated herein.

In certain embodiments presented herein are antagonists of DP₂ that havea structure of Formula (I), Formula (II), Formula (III), Formula (IV)and Formula (V) are antagonists of DP₂. In specific embodiments, theantagonist of DP₂ is selective for DP₂. In other embodiments, theantagonist of DP₂ is also an antagonist of DP₁. In some embodiments, theantagonist of DP₂ is also an antagonist of TP (thromboxane receptor).

In other embodiments, presented herein are compounds selected fromactive metabolites, solvates, pharmaceutically acceptable salts orpharmaceutically acceptable prodrugs of a compound of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V).

In one aspect, provided herein is a pharmaceutical compositioncomprising a therapeutically effective amount of a compound providedherein. In some embodiments, the pharmaceutical composition alsocontains a pharmaceutically acceptable excipient.

In certain embodiments, presented herein are methods for treating aPGD₂-dependent condition or disease in a patient comprisingadministering to the patient a therapeutically effective amount of anantagonist of DP₂ having the structure of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V).

In certain aspects, provided herein is a method for treatinginflammation in a mammal comprising administering a therapeuticallyeffective amount of a compound provided herein to the mammal in need.

In a specific aspect, provided herein is a method for treating asthma ina mammal comprising administering a therapeutically effective amount ofa compound provided herein to the mammal in need. In a further oralternative embodiment, provided herein is a method for treating asthmain a mammal comprising administering a therapeutically effective amountof a compound provided herein, such as, for example, a compound ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V),to the mammal in need.

In another aspect are compounds presented in Table 1 and Table 2 orpharmaceutically acceptable salts, pharmaceutically active metabolites,pharmaceutically acceptable prodrugs, and pharmaceutically acceptablesolvates thereof, which antagonize DP₂ and are used to treat patientssuffering from one or more PGD₂-dependent conditions or diseases,including, but not limited to, asthma, rhinitis, chronic obstructivepulmonary disease, pulmonary hypertension, interstitial lung fibrosis,arthritis, allergy, psoriasis, inflammatory bowel disease, adultrespiratory distress syndrome, myocardial infarction, aneurysm, stroke,cancer, endotoxic shock, proliferative disorders and inflammatoryconditions.

In one aspect, the compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V), including pharmaceuticallyacceptable salts, pharmaceutically acceptable prodrugs, andpharmaceutically acceptable solvates thereof, are antagonists of CRTH2.In various embodiments presented herein, these compounds are used totreat patients suffering from one or more PGD₂-dependent conditions ordiseases, including, but not limited to, asthma, rhinitis, chronicobstructive pulmonary disease, pulmonary hypertension, interstitial lungfibrosis, rhinitis, allergy, and adult respiratory distress syndrome.

In one aspect, the compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are antagonists of DP₂. In stillfurther or alternative embodiments such antagonists of DP₂ alsoantagonize other related PGD₂ receptors. Related PGD₂ receptors include,but are not limited to, DP₁ and TP.

In one aspect, the compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are administered with a TPantagonist. TP antagonists inhibit bronchoconstriction,vasoconstriction, and platelet aggregation. In one aspect,co-administration of a TP antagonist with a compound of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V) inhibitsbronchoconstrictor effects of PGD₂ and other prostanoids.

In further or alternative embodiments, the compounds of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V) are includedinto pharmaceutical compositions or medicaments used for treating aPGD₂-dependent or PGD₂ mediated condition or disease in a patient.

The pharmaceutical formulations described herein are administered to asubject by multiple administration routes, including but not limited to,oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical or transdermal administration routes. Thepharmaceutical formulations described herein include, but are notlimited to, aqueous liquid dispersions, self-emulsifying dispersions,solid solutions, liposomal dispersions, aerosols, solid dosage forms,powders, immediate release formulations, controlled releaseformulations, fast melt formulations, tablets, capsules, pills, delayedrelease formulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate andcontrolled release formulations.

In some embodiments, the compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are administered orally.

In some embodiments, the compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are administered topically. In suchembodiments, the compound of Formula (I), Formula (II), Formula (III),Formula (IV) or Formula (V) is formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, medicated bandages, shampoos, rubs,scrubs, smears, balms, creams or ointments. Such pharmaceuticalcompounds optionally contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives.

In another aspect, the compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are administered by intranasaladministration.

In another aspect, the compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are formulated for intranasaladministration. Such formulations include nasal sprays, nasal mists,nasal gels, and the like.

In another aspect, the compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are formulated as eye drops.

In one aspect, the compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are administered topically to theskin.

In another aspect, compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are used to treat or preventinflammatory conditions. Inflammatory conditions include, but are notlimited to, asthma, rhinitis, chronic obstructive pulmonary disease,pulmonary hypertension, interstitial lung fibrosis, atherosclerosis,aortic aneurysm, myocardial infarction, and stroke.

In another aspect, compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are used to treat or preventimmunological disorders. In one aspect the immunological disordersinclude, but are not limited to, allergy or to excessive orinappropriate response to an endogenous or exogenous antigen. In certainembodiments, the immunological disorder that is characterized by immunedysregulation that is not accompanied by inflammation.

In another aspect, compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are used to treat or preventproliferative disorders. In one aspect the proliferative disordersinclude, but are not limited to, cancer and noncancerous disorders,including, but not limited to, those involving the skin or lymphatictissues.

In additional aspects, such conditions are iatrogenic and increases in,or abnormal localization of, PGD₂ is induced by other therapies ormedical or surgical procedures. In other embodiments, the PGD₂-dependentor PGD₂ mediated condition or disease is caused by surgery.

In other aspects, the methods, compounds, pharmaceutical compositions,and medicaments described herein are used to prevent the cellularactivity of PGD₂. In other aspects, such methods, compounds,pharmaceutical compositions, and medicaments comprise DP₂ antagonistsdisclosed herein for the treatment of asthma by modulating the activityof enzymes or proteins in a patient wherein such enzymes or proteins areinvolved in the PGD₂ pathway such as, by way of example, DP₂. In yetother aspects, the methods, compounds, pharmaceutical compositions, andmedicaments described herein are used in combination with other medicaltreatments or surgical modalities.

In one aspect are methods for reducing/antagonizing the PGD₂ activationof DP₂ in a mammal comprising administering to the mammal at least oncean effective amount of a compound having the structure of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V).

In another aspect are methods for modulating, including reducing and/orantagonizing the activation of DP₂, directly or indirectly, in a mammalcomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (I), Formula(II), Formula (III), Formula (IV) or Formula (V).

In another aspect, presented herein are methods for modulating,including reducing and/or antagonizing the activity of PGD₂ in a mammal,directly or indirectly, comprising administering to the mammal at leastonce an effective amount of at least one compound having the structureof Formula (I), Formula (II), Formula (III), Formula (IV) or Formula(V).

In another aspect are methods for treating PGD₂-dependent or PGD₂mediated conditions or diseases, comprising administering to the mammalat least once an effective amount of at least one compound having thestructure of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V).

In another aspect are methods for treating inflammation comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V).

In another aspect are methods for treating immunological abnormalitiescomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (I), Formula(II), Formula (III), Formula (IV) or Formula (V).

In another aspect are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (I), Formula(II), Formula (III), Formula (IV) or Formula (V). In a furtherembodiment of this aspect, the respiratory disease is asthma. In afurther embodiment of this aspect, the respiratory disease includes, butis not limited to, adult respiratory distress syndrome and allergic(extrinsic) asthma, non-allergic (intrinsic) asthma, acute severeasthma, chronic asthma, clinical asthma, nocturnal asthma,allergen-induced asthma, aspirin-sensitive asthma, exercise-inducedasthma, isocapnic hyperventilation, child-onset asthma, adult-onsetasthma, cough-variant asthma, occupational asthma, steroid-resistantasthma, seasonal asthma.

In another aspect are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (I), Formula(II), Formula (III), Formula (IV) or Formula (V). In a furtherembodiment of this aspect, the respiratory disease is rhinitis. In afurther embodiment of this aspect, the respiratory disease includes, butis not limited to, allergic (extrinsic) rhinitis, non-allergic(intrinsic) rhinitis, chronic rhinitis, allergen-induced rhinitis,aspirin-sensitive rhinitis, child-onset rhinitis, adult-onset rhinitis,occupational rhinitis, steroid-resistant rhinitis, seasonal rhinitis,perennial rhinitis, rhinosinusitis, and rhinopolyposis.

In another aspect are methods for treating chronic obstructive pulmonarydisease comprising administering to the mammal at least once aneffective amount of at least one compound having the structure ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V).In a further embodiment of this aspect, chronic obstructive pulmonarydisease includes, but is not limited to, chronic bronchitis and/oremphysema, pulmonary hypertension, interstitial lung fibrosis and/orairway inflammation and cystic fibrosis.

In another aspect are methods for preventing increased mucosal secretionand/or edema in a disease or condition comprising administering to themammal at least once an effective amount of at least one compound havingthe structure of Formula (I), Formula (II), Formula (III), Formula (IV)or Formula (V).

In another aspect are methods for treating vasoconstriction,atherosclerosis and its sequelae myocardial ischemia, myocardialinfarction, aortic aneurysm, vasculitis, cardiac arrhythmia, and strokecomprising administering to the mammal an effective amount of a compoundhaving the structure of Formula (I), Formula (II), Formula (III),Formula (IV) or Formula (V).

In another aspect are methods for treating organ reperfusion injuryfollowing organ ischemia and/or endotoxic shock comprising administeringto the mammal at least once an effective amount of at least one compoundhaving the structure of Formula (I), Formula (II), Formula (III),Formula (IV) or Formula (V).

In another aspect are methods for reducing the constriction of bloodvessels in a mammal comprising administering to the mammal at least oncean effective amount of at least one compound having the structure ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V).

In another aspect are methods for lowering or preventing an increase inblood pressure of a mammal comprising administering to the mammal atleast once an effective amount of at least one compound having thestructure of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V).

In another aspect are methods for preventing eosinophil and/or basophiland/or dendritic cell and/or neutrophil and/or monocyte or Th2 cellrecruitment comprising administering to the mammal at least once aneffective amount of at least one compound having the structure ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V).

A further aspect are methods for the prevention or treatment of abnormalbone remodeling, loss or gain, including diseases or conditions as, byway of example, osteopenia, osteoporosis, Paget's disease, cancer,trauma, surgery, and other diseases comprising administering to themammal at least once an effective amount of at least one compound havingthe structure of Formula (I), Formula (II), Formula (III), Formula (IV)or Formula (V).

In another aspect are methods for preventing ocular inflammation andallergic conjunctivitis, vernal keratoconjunctivitis, and papillaryconjunctivitis comprising administering to the mammal at least once aneffective amount of at least one having the structure of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V).

In another aspect are methods for treating CNS disorders comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V). CNS disorders include, butare not limited to, multiple sclerosis, Parkinson's disease, Alzheimer'sor other degenerative disease, stroke, cerebral ischemia, retinalischemia, post-surgical cognitive dysfunction, migraine, peripheralneuropathy/neuropathic pain, spinal cord injury, cerebral edema and headinjury.

In another aspect are methods for treating pain comprising administeringto the mammal at least once an effective amount of at least one compoundhaving the structure of Formula (I), Formula (II), Formula (III),Formula (IV) or Formula (V).

A further aspect are methods for the treatment of cancer comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V). The type of cancer includes,but is not limited to, pancreatic cancer and other solid orhematological tumors.

In another aspect are methods for treating endotoxic shock and septicshock comprising administering to the mammal at least once an effectiveamount of at least one compound having the structure of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V).

In another aspect are methods for treating rheumatoid arthritis andosteoarthritis comprising administering to the mammal at least once aneffective amount of at least one compound having the structure ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V).

In another aspect are methods for treating or preventing increasedgastrointestinal diseases comprising administering to the mammal atleast once an effective amount of at least one compound having thestructure of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V). Such diseases include, by way of example only, chronicgastritis, eosinophilic gastroenteritis, and gastric motor dysfunction.

A further aspect are methods for treating kidney diseases comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V). Such diseases include, byway of example only, acute tubular necrosis, glomerulonephritis,cyclosporine nephrotoxicity, renal ischemia, and reperfusion injury.

In another aspect are methods for preventing or treating acute orchronic renal insufficiency comprising administering to the mammal atleast once an effective amount of at least one compound having thestructure of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V).

In another aspect are methods to diminish the inflammatory aspects ofacute infections within one or more solid organs or tissues such as thekidney with acute pyelonephritis.

In another aspect are methods for preventing or treating acute orchronic disorders involving recruitment or activation of eosinophilscomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (I), Formula(II), Formula (III), Formula (IV) or Formula (V).

In another aspect are methods for preventing or treating acute orchronic erosive disease or motor dysfunction of the gastrointestinaltract caused by non-steroidal anti-inflammatory drugs (includingselective or non-selective cyclooxygenase-1 or -2 inhibitors) comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V).

A further aspect are methods for the prevention or treatment ofrejection or dysfunction in a transplanted organ or tissue comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V).

In another aspect are methods for treating inflammatory responses of theskin comprising administering to the mammal at least once an effectiveamount of at least one compound having the structure of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V). Suchinflammatory responses of the skin include, by way of example,dermatitis, contact dermatitis, eczema, urticaria, rosacea, andscarring. In another aspect are methods for reducing psoriatic lesionsin the skin, joints, or other tissues or organs, comprisingadministering to the mammal an effective amount of a first compoundhaving the structure of Formula (I), Formula (II), Formula (III),Formula (IV) or Formula (V).

A further aspect are methods for the treatment of cystitis, including,by way of example only, interstitial cystitis, comprising administeringto the mammal at least once an effective amount of at least one compoundhaving the structure of Formula (I), Formula (II), Formula (III),Formula (IV) or Formula (V).

A further aspect are methods for the treatment of Familial MediterraneanFever comprising administering to the mammal at least once an effectiveamount of at least one compound having the structure of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V).

In a further aspect are methods to treat hepatorenal syndrome comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V).

In a further aspect are methods to modulate the immune response toendogenous or exogenous antigens.

In a further aspect are methods to treat acute or chronic allergicresponses to exogenous substances that have been ingested such as foods(e.g., peanuts) or drugs (e.g., penicillin, non-steroidalanti-inflammatory drugs or the like).

In another aspect is the use of a compound of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) in the manufacture of amedicament for treating an inflammatory disease or condition in ananimal in which the activity of at least one PGD₂-associated proteincontributes to the pathology and/or symptoms of the disease orcondition. In one embodiment of this aspect, the PGD₂ pathway protein isCRTH2. In another or further embodiment of this aspect, the inflammatorydisease or conditions are respiratory, cardiovascular, or proliferativediseases.

In any of the aforementioned aspects are further embodiments in which:(a) the effective amount of the compound is systemically administered tothe mammal; and/or (b) the effective amount of the compound isadministered orally to the mammal; and/or (c) the effective amount ofthe compound is intravenously administered to the mammal; and/or (d) theeffective amount of the compound administered by inhalation; and/or (e)the effective amount of the compound is administered by nasaladministration; or and/or (f) the effective amount of the compound isadministered by injection to the mammal; and/or (g) the effective amountof the compound is administered topically (dermal) to the mammal; and/or(h) the effective amount of the compound is administered by ophthalmicadministration; and/or (i) the effective amount of the compound isadministered rectally to the mammal

In any of the aforementioned aspects are further embodiments in whichthe mammal is a human, including embodiments wherein the human has anasthmatic condition or one or more other condition(s) selected from thegroup consisting of allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitiveasthma, exercise-induced asthma, isocapnic hyperventilation, child-onsetasthma, adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, or seasonal asthma, or chronic obstructivepulmonary disease, or pulmonary hypertension or interstitial lungfibrosis. In any of the aforementioned aspects are further embodimentsin which the mammal is an animal model for pulmonary inflammation,examples of which are provided herein.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce daily; (ii) the compound is administered twice daily; (iii) thecompound is administered in cycles that include daily administration fora period of time followed by at least 1 day without administration; (iv)the compound is administered in cycles that include daily administrationfor a period of time followed by at least 1 day that includes a dosereduction in the daily amount of compound that is administered.

In any of the aforementioned aspects involving the treatment of PGD₂dependent diseases or conditions are further embodiments comprisingadministering at least one additional agent in addition to theadministration of a compound having the structure of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V). In variousembodiments, each agent is administered in any order, includingsimultaneously. In certain embodiments, the at least one additionalagent is, by way of example only, an anti-inflammatory agent, adifferent compound having the structure of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V), a DP₁ receptor antagonist, aTP receptor antagonist, or a different DP₂ receptor antagonist.

In other embodiments, a compound of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) is combined with an additional agentthat is a respiratory agent, including, but not limited toantihistamines (e.g., Zyrtec®), bronchodilators, LABAs (e.g.,salmeterol), theophylline, IgE modulators (e.g., Xolair® andomalizumab), steroids (e.g., fluticasone).

In further or alternative embodiments, the anti-inflammatory agent is,by way of example only, a leukotriene pathway modulator such as a CysLT1receptor antagonists (e.g., montelukast), a CysLT2 receptor antagonist,a 5-lipoxygenase inhibitor (e.g., zileuton), a 5-lipoxygenase-activatingprotein inhibitor (e.g., MK-0591, MK-886, DG-031 (BAY X1005),3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid,3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid), a LTA4 hydrolase inhibitor, a LTC₄ synthase inhibitor or a BLT1receptor antagonist.

In any of the aforementioned aspects involving the treatment ofproliferative disorders, including cancer, are further embodimentscomprising administering at least one additional agent, including by wayof example only alemtuzumab, arsenic trioxide, asparaginase (pegylatedor non-), bevacizumab, cetuximab, platinum-based compounds such ascisplatin, cladribine, daunorubicin/doxorubicin/idarubicin, irinotecan,fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, Paclitaxel™,taxol, temozolomide, thioguanine, or classes of drugs including hormones(an antiestrogen, an antiandrogen, or gonadotropin releasing hormoneanalogues, interferons such as alpha interferon, nitrogen mustards suchas busulfan or melphalan or mechlorethamine, retinoids such astretinoin, topoisomerase inhibitors such as irinotecan or topotecan,tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents totreat signs or symptoms induced by such therapy including allopurinol,filgrastim, granisetron/ondansetron/palonosetron, dronabinol.

In any of the aforementioned aspects involving the therapy of animmunological disorder requiring immunosuppression or involving thetherapy of transplanted organs or tissues or cells are furtherembodiments comprising administering at least one additional agent,including by way of example only azathioprine, a corticosteroid,cyclophosphamide, cyclosporin, dacluzimab, mycophenolate mofetil, OKT3,rapamycin, tacrolimus, or thymoglobulin.

In any of the aforementioned aspects involving the therapy ofinterstitial cystitis are further embodiments comprising administeringat least one additional agent selected from, e.g., dimethylsulfoxide,omalizumab, and pentosan polysulfate.

In any of the aforementioned aspects involving the therapy of disordersof bone are further embodiments comprising administering at least oneadditional agent such as, by way of example only, minerals, vitamins,bisphosphonates, anabolic steroids, parathyroid hormone or analogs, andcathepsin K inhibitors dronabinol.

In any of the aforementioned aspects involving the prevention ortreatment of inflammation are further embodiments comprising: (a)monitoring inflammation in a mammal; (b) measuring bronchoconstrictionin a mammal; (c) measuring eosinophil and/or basophil and/or dendriticcell and/or neutrophil and/or monocyte and/or lymphocyte recruitment ina mammal; (d) monitoring mucosal secretion in a mammal; (e) measuringmucosal edema in a mammal.

In any of the aforementioned aspects the PGD₂-dependent or PGD₂ mediateddiseases or conditions include, but are not limited to, asthma,rhinitis, chronic obstructive pulmonary disease, pulmonary hypertension,interstitial lung fibrosis, arthritis, allergy, inflammatory boweldisease, adult respiratory distress syndrome, myocardial infarction,aneurysm, stroke, cancer, and endotoxic shock.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Prostaglandin D₂ (PGD₂) is an acidic lipid derived from the metabolismof arachidonic acid by cyclooxygenases and PGD₂ synthases. PGD₂ isproduced by mast cells, macrophages and Th2 lymphocytes in response tolocal tissue damage as well as in response allergic inflammationobserved in diseases such as asthma, rhinitis, and atopic dermatitis.More specifically, exogenous PGD₂ applied to bronchial airways elicitsmany responses that are characteristic of acute asthma.

PGD₂ is a major mast cell product that acts via two receptors, theD-type prostanoid (DP, also known as DP₁) and the chemoattractantreceptor-homologous molecule expressed on Th2 cells (CRTH2, also knownas DP₂) receptors. DP₂ mediates the chemotaxis of eosinophils,basophils, and Th2 lymphocytes, and DP₁ receptor plays an important rolein eosinophil trafficking. DP₁ antagonists do not inhibit the release ofeosinophils when induced by the DP₂-selective agonists. However,eosinophils in human bone marrow specimens express DP₁ and DP₂ receptorsat similar levels and human peripheral blood expresses both DP₁ and DP₂,but the DP₁ receptor is expressed at lower levels. In agreement withthis, the chemotaxis of human peripheral blood eosinophils is inhibitedby both DP₁ and DP₂ antagonists. Accordingly, DP₁, DP₂ and dual DP₁/DP₂antagonists are useful in the treatment of allergic inflammation.

Activation of DP₂ is associated with chemotaxis and activation of Th2lymphocytes, eosinophils and basophils. In particular, PGD₂ binds to DP₂and mediates many of its effects through a G_(i)-dependent elevation ofintracellular calcium levels and reduction of cyclic AMP. In Th2lymphocytes, IL4, IL5 and IL13 cytokine production are also stimulatedby DP₂ activation. These cytokines have been implicated in numerousbiological actions including, by way of example only, immunoglobulin Eproduction, airway response, mucous secretion, and eosinophilrecruitment.

The terms CRTH2 and DP₂, refer to the same receptor and are usedinterchangeably herein. Likewise, another common name for DP is DP₁, andthe two terms are used interchangeably herein.

Illustrative Biological Activity

Prostaglandins (PGs) are recognized physiological lipid acid mediatorsproduced by the release of arachidonic acid from cell membranephospholipids and converted to prostaglandins by the action of COX₁ andCOX₂ cyclooxygenases and PG synthases. The cyclooxygenases sequentiallyconvert arachidonic acid to cyclic endoperoxide prostaglandin G₂ (PGG₂)and subsequently, prostaglandin H₂ (PGH₂). Depending on the tissue,physiological signal, and/or synthase type, PGH₂ can be converted tonumerous different prostaglandins, such as PGE₂, PGD₂, PGF₂α, and PGI₂as well as thromboxane A₂, another eicosanoid signaling molecule. Thesemediators then elicit a wide variety of physiological responsesincluding vasoconstriction or dilation, platelet aggregation, calciumtransport, pain sensitization, hormone release, inflammatory and immuneresponse, and cellular growth.

Prostaglandin D₂ is a major metabolite produced from the PGH₂intermediate via hematopoietic PGD₂ synthase or lipocalin PGD₂ synthase.In the brain and central nervous system, PGD₂ is produced and thought tofunction in pain perception and sleep regulation. In other tissues, PGD₂is produced primarily in immunoglobulin E (IgE) activated mast cells andto a lesser extent, in macrophages, dendritic cells, T helper 2 (Th2)lymphocytes and other leukocytes. In the cell, PGD₂ is rapidlymetabolized and converted to other downstream effectors includingΔ¹²PGJ₂, 9α11βPGF₂, 13,14-dihydro-15-keto-PGD₂, and15-deoxy-Δ^(12,14)PGD₂.

Mast-cell-derived PGD₂ is produced in high concentrations in response toan allergen challenge. Studies in preclinical species have observed thefollowing features when PGD₂ is applied to in vivo preparations, or itsoverproduction is engineered by genetic manipulation:

-   -   Vasodilatation leading to erythema (flare) and -potentiation of        oedema (wheal).    -   Recruitment of eosinophils and Th2 lymphocytes.    -   Modulation of Th2-cytokine production.    -   Bronchoconstriction.

Injection of PGD₂ into human skin has been shown to produce a longlasting erythema, to potentiate the effects of other mediators oninduration and leukocyte infiltration in human skin and to enhanceoedema formation in rat skin. It is most likely that these effects ofPGD₂, like those of other vasodilator prostaglandins, are due to anincreased blood flow to the inflamed lesion and are, therefore, mostlikely to be mediated predominantly by the DP₁ receptor. Although theseobservations make it clear that DP₁ mediates the vascular effects ofPGD₂, the capacity of PGD₂ to promote the cellular changes associatedwith inflammation is not due to an action on DP₁.

The main receptors that are activated by PGD₂ or its metabolites andmediate its effects are DP₁, CRTH2 (or DP₂) and TP.

DP₁ (or DP) is a G-protein coupled seven-transmembrane receptor that,upon activation by PGD₂ binding, leads to an increase in intracellularcAMP levels. DP₁ is expressed in the brain, bronchial smooth muscle,vascular and airway smooth muscle, dendritic cells, and platelets andinduces PGD₂ dependent bronchodilation, vasodilation, plateletaggregation inhibition, and suppression of cytokine production. Geneticanalysis of DP₁ function using knock-out mice has shown that micelacking DP do not develop asthmatic responses in an ovalbumin-inducedasthma model. Analysis of selective DP anatgonists in guinea pigallergic rhinitis models demonstrated dramatic inhibition of early nasalresponses, as assessed by sneezing, mucosal plasma exudation andeosinophil infiltration. DP antagonism alleviate allergen-induced plasmaexudation in the conjunctiva in a guinea pig allergic conjuctivitismodel and antigen-induced esinophil infiltration into the lung in aguinea pig asthma model.

Much of PGD₂'s pro-inflammatory activity is through interaction with DP₂(or CRTH2). DP₂ is a G-protein coupled receptor and is typically highlyexpressed in Th2 lymphocytes, eosinophils and basophils. DP₂ activationfunctions to directly activate and recruit Th2 lymphocytes andeosinophils. Activated Th2 lymphocytes produce and secrete inflammatorycytokines including IL4, IL5, and IL13. Despite binding PGD₂ with asimilar affinity as DP₁, DP₂ is not structurally related to DP₁ andsignals through a different mechanism—the effects of DP₂ are mediatedthrough Gi-dependent elevation in intracellular calcium levels andreduction in intracellular levels of cyclic AMP. DP₂ activation isimportant in eosinophil recruitment in response to allergic challenge insuch tissues as nasal mucosa, bronchial airways, and skin. Theapplication of either PGD₂ or selective DP₂ agonists both exacerbate andenhance allergic responses in lung and skin. DP₂ activation appears tohave a crucial role in mediating allergic responses, and thus the use ofantagonists of PGD₂ activation of the DP₂ receptor are an attractiveapproach to treat the inflammatory component of allergic diseases suchas asthma, rhinitis, and dermatitis.

TP receptors primarily function to antagonize DP₁ receptor's effectssuch as promoting bronchoconstriction, vasoconstriction, and plateletaggregation. While TP receptor's main ligand is thromboxane A₂, it alsobinds and is activated by the PGD₂ derivative, 9α11βPGF₂. TP is aGq-coupled prostanoid receptor that binds thromboxane with highaffinity, promoting platelet aggregation and constriction of bothvascular and airway smooth muscle. PGD₂ activates the TP receptor inhuman bronchial muscle, probably through the formation of the11-ketoreductase metabolite 9α11βPGF2. The bronchoconstrictor effects ofTP dominate over the bronchodilator effects of DP₁ in the airways.

DP₁ and DP₂ have crucial, and complementary, roles in the physiologicalresponse of animals to PGD₂ and blockade of either one or both of thesereceptors may prove beneficial in alleviating allergic diseases orconditions triggered by PGD₂, such as, but not limited to, allergicrhinitis, asthma, dermatitis, and allergic conjunctivitis.

Compounds

Compounds of any of Formula (I), Formula (II), Formula (III), Formula(IV) or

Formula (V), including pharmaceutically acceptable salts,pharmaceutically acceptable prodrugs, and pharmaceutically acceptablesolvates thereof, antagonize or modulate DP₂ and are used to treatpatients suffering from PGD₂-dependent or PGD₂ mediated conditions ordiseases, including, but not limited to, asthma, rhinitis, dermatitis,and inflammatory conditions.

In one aspect is a compound having the structure of Formula (I),pharmaceutically acceptable salts, pharmaceutically acceptable solvates,N-oxides, or pharmaceutically acceptable prodrugs thereof:

wherein,

-   -   ring B is a substituted or unsubstituted heteroaryl, wherein if        ring B is substituted, then each substituent on ring B is        independently selected from H and R^(B);    -   X is a bond, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR¹³—, —CH₂—, or        —C(═O)—;    -   Q is —C(═O)-Q¹, tertrazolyl, or a carboxylic acid bioisostere;        -   Q¹ is —OH, —OR¹⁵, —NHSO₂R⁹, —N(R¹⁰)₂, —NH—OH, or —NH—CN;    -   each R¹ is independently selected from H, halogen, C₁-C₄alkyl,        and C₁-C₄haloalkyl; or    -   both R¹ groups taken together with the carbon atom to which they        are attached form a C₃-C₆cycloalkyl;    -   each of R², R³, R⁴, R⁵ and R^(B) is independently selected from        H, halogen, —CN, —NO₂, —OH, —OR¹⁰, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹,        —N(R¹⁰)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰,        —OCO₂R¹⁰, —N(R¹⁰)₂, —NHCH₂CO₂R¹⁰, —OCH₂CO₂R¹⁰, —SCH₂CO₂R¹⁰,        —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NR¹⁰C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹,        —NR¹⁰—C₁-C₄alkyl-C(═O)R⁹, —NR¹⁰C(═O)OR⁹, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy,        C₁-C₆heteroalkyl, a substituted or unsubstituted cycloalkyl, a        substituted or unsubstituted heterocycloalkyl, a substituted or        unsubstituted aryl, a substituted or unsubstituted heteroaryl, a        substituted or unsubstituted —C₁-C₆alkyl-cycloalkyl, a        substituted or unsubstituted —C₁-C₆alkyl-heterocycloalkyl, a        substituted or unsubstituted —C₁-C₆alkyl-aryl, and a substituted        or unsubstituted-C₁-C₆alkyl-heteroaryl;    -   each R⁶ is each independently selected from H, halogen,        C₁-C₄alkyl, and C₁-C₄haloalkyl; or    -   both R⁶ groups are taken together with the carbon atom to which        they are attached to form a C₃-C₆cycloalkyl;    -   R⁷ is —C(═O)R¹¹, —C(═O)OR¹², —C(═O)N(R¹³)₂, —S(═O)₂N(R¹³)₂ or        —S(═O)₂R¹²;        -   R¹¹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a            substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted            or unsubstituted heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted            heteroaryl, a substituted or unsubstituted            —C₁-C₆alkyl-cycloalkyl, a substituted or unsubstituted            —C₁-C₆alkyl-heterocycloalkyl, a substituted or unsubstituted            —C₁-C₆alkyl-aryl or a substituted or unsubstituted            —C₁-C₆alkyl-heteroaryl; or        -   R¹¹ is L³-X³-Q³;            -   L³ is a C₁-C₆alkylene;            -   X³ is a bond, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR¹³—;            -   Q³ is a C₁-C₆alkyl, C₁-C₆fluoroalkyl a substituted or                unsubstituted C₃-C₁₀cycloalkyl, a substituted or                unsubstituted heterocycloalkyl, a substituted or                unsubstituted aryl, a substituted or unsubstituted                heteroaryl, a substituted or unsubstituted                C₁-C₆alkyl-C₃-C₁₀cycloalkyl, a substituted or                unsubstituted C₁-C₆alkyl-heterocycloalkyl, a substituted                or unsubstituted C₁-C₆alkyl-aryl, or a substituted or                unsubstituted C₁₋₆alkyl-heteroaryl;        -   R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a            substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted            or unsubstituted heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted            heteroaryl, a substituted or unsubstituted            —C₁-C₆alkyl-cycloalkyl, a substituted or unsubstituted            —C₁-C₆alkyl-heterocycloalkyl, a substituted or unsubstituted            —C₁-C₆alkyl-aryl or a substituted or unsubstituted            —C₁-C₆alkyl-heteroaryl;        -   each R¹³ is independently H, —CN, C₁-C₆alkyl,            C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or            unsubstituted C₃-C₁₀cycloalkyl, a substituted or            unsubstituted heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted            heteroaryl, a substituted or unsubstituted —C₁-C₆alkyl            -cycloalkyl, a substituted or unsubstituted            —C₁-C₆alkyl-heterocycloalkyl, a substituted or unsubstituted            —C₁-C₆alkyl-aryl or a substituted or unsubstituted            —C₁-C₆alkyl-heteroaryl; or        -   two R¹³ groups attached to the same N atom are taken            together with the N atom to which they are attached to form            a substituted or unsubstituted heterocycle;    -   R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, (a        substituted or unsubstituted monocyclic or bicyclic cycloalkyl),        (a substituted or unsubstituted monocyclic or bicyclic        heterocycloalkyl), a substituted or unsubstituted aryl, or a        substituted or unsubstituted heteroaryl, C₁-C₆alkylene-R¹⁴,        —C₁-C₆alkylene-O—R¹⁴, —C₁-C₆alkylene-S—R¹⁴,        —C₁-C₆alkylene-S(═O)—R¹⁴, —C₁-C₆alkylene-S(═O)₂—R¹⁴,        —C₁-C₆alkylene-N(R¹⁴)₂, —C₁-C₆alkylene-C(═O)—R¹⁴,        —C₁-C₆alkylene-C(═O)O—R¹⁴—, —C₁-C₆alkylene-OC(═O)—R¹⁴,        —C₁-C₆alkylene-NR¹⁴C(═O)—R¹⁴ or —C₁-C₆alkylene-C(═O)N(R¹⁴)₂;        -   each R¹⁴ is independently selected from H, C₁-C₆alkyl,            C₁-C₆heteroalkyl, C₁-C₆haloalkyl, a substituted or            unsubstituted cycloalkyl, a substituted or unsubstituted            heterocycloalkyl, a substituted or unsubstituted aryl, a            substituted or unsubstituted benzyl, or a substituted or            unsubstituted heteroaryl;    -   R⁹ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a        substituted or unsubstituted cycloalkyl, a substituted or        unsubstituted heterocycloalkyl, a substituted or unsubstituted        aryl, a substituted or unsubstituted benzyl, a substituted or        unsubstituted heteroaryl, a substituted or unsubstituted        —C₁-C₄alkyl-cycloalkyl, a substituted or unsubstituted        —C₁-C₄alkyl-heterocycloalkyl, a substituted or unsubstituted        —C₁-C₄alkyl-aryl, or a substituted or unsubstituted        —C₁-C₄alkyl-heteroaryl;    -   each R¹⁰ is independently selected from H, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a substituted or        unsubstituted cycloalkyl, a substituted or unsubstituted        heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted benzyl, a substituted or        unsubstituted heteroaryl, a substituted or unsubstituted        —C₁-C₄alkyl-cycloalkyl, a substituted or unsubstituted        —C₁-C₄alkyl-heterocycloalkyl, a substituted or unsubstituted        —C₁-C₄alkyl-aryl, and a substituted or unsubstituted        —C₁-C₄alkyl-heteroaryl; or    -   two R¹⁰ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted heterocycloalkyl; and    -   each R¹⁵ is independently selected from H and C₁-C₆alkyl.

For any and all of the embodiments, substituents can be selected fromamong from a subset of the listed alternatives.

In some embodiments, X is a bond, —O—, or —CH₂—. In other embodiments, Xis a bond. In other embodiments, X is —O—. In some other embodiments, Xis —CH₂—.

In any embodiment, if ring B is substituted, then ring B is substitutedwith one or two R^(B) groups.

In some embodiments, ring B is a substituted or unsubstituted monocyclicheteroaryl ring or a substituted or unsubstituted bicyclic heteroarylring, where ring B contains 0-1 oxygen atoms; 0-1 sulfur atoms; and 0-4nitrogen atoms, wherein if ring B is substituted, then each substituenton ring B is independently selected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstituted monocyclicheteroaryl ring or a substituted or unsubstituted bicyclic heteroarylring, where ring B contains 0-1 oxygen atoms; 0-1 sulfur atoms; and 0-4nitrogen atoms, wherein if ring B is substituted, then ring B issubstituted with one or two R^(B).

In other embodiments, ring B is a substituted or unsubstitutedheteroaryl ring selected from pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl,isoxazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl, tetrazolyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl,benzothienyl, benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl,phthalazinyl, pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl,azaindolyl, pyrazolopyridinyl, thiazolopyrimidinyl, thiazolopyridinyl,pyridothienyl, pyrimidiothienyl and pyrrolopyrimidinyl, wherein if ringB is substituted, then each substituent on ring B is independentlyselected from H and R^(B).

In some other embodiments, ring B is a substituted or unsubstitutedmonocyclic heteroaryl ring, where ring B contains 0-1 oxygen atoms; 0-1sulfur atoms; and 1-3 nitrogen atoms, wherein if ring B is substituted,then each substituent on ring B is independently selected from H andR^(B).

In some embodiments, ring B is a substituted or unsubstituted heteroarylring selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl,pyrazolyl, isothiazolyl, triazolyl, and tetrazolyl, wherein if ring B issubstituted, then each substituent on ring B is independently selectedfrom H and R^(B). In some embodiments, ring B is a substituted orunsubstituted heteroaryl ring selected from pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thiazolyl, oxazolyl,isoxazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl, andtetrazolyl, wherein if ring B is substituted, then ring B is substitutedwith one or two R^(B).

In some embodiments, ring B is a substituted or unsubstituted 6-memberedmonocyclic heteroaryl ring, where ring B contains 1-3 nitrogen atoms,wherein if ring B is substituted, then each substituent on ring B isindependently selected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstituted 6-memberedmonocyclic heteroaryl ring, where ring B contains 1 or 2 nitrogen atoms,wherein if ring B is substituted, then each substituent on ring B isindependently selected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstituted heteroarylring selected from pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl,wherein if ring B is substituted, then each substituent on ring B isindependently selected from H and R^(B). In some embodiments, ring B isa substituted or unsubstituted heteroaryl ring selected from pyridinyl,pyrimidinyl, pyridazinyl, and pyrazinyl, wherein if ring B issubstituted, then ring B is substituted with one or two R^(B).

In some embodiments, ring B is a substituted or unsubstitutedsubstituted or unsubstituted bicyclic heteroaryl ring, where ring Bcontains 0-1 oxygen atoms; 0-1 sulfur atoms; and 0-4 nitrogen atoms,wherein if ring B is substituted, then each substituent on ring B isindependently selected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstituted bicyclicheteroaryl selected from quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl,benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl,pyridopyrimidinyl, pyrazolopyrimidinyl, azaindolyl, pyrazolopyridinyl,thiazolopyrimidinyl, thiazolopyridinyl, pyridothienyl, pyrimidiothienyland pyrrolopyrimidinyl, wherein if ring B is substituted, then eachsubstituent on ring B is independently selected from H and R^(B).

In some embodiments, ring B is a substituted or unsubstituted bicyclicheteroaryl selected from quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl,benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl,pyridopyrimidinyl, pyrazolopyrimidinyl, azaindolyl, pyrazolopyridinyl,thiazolopyrimidinyl, thiazolopyridinyl, pyridothienyl, pyrimidiothienyland pyrrolopyrimidinyl, wherein if ring B is substituted, then ring B issubstituted with one or two R^(B).

In some embodiments, ring B is a substituted or unsubstitutedsubstituted or unsubstituted bicyclic heteroaryl ring, where ring Bcontains 0-1 oxygen atoms; 0-1 sulfur atoms; and 1-4 nitrogen atoms,wherein if ring B is substituted, then each substituent on ring B isindependently selected from H and R^(B).

In some embodiments, the groups

are on adjacent atoms of ring B.

In some embodiments, the groups

are on adjacent carbon atoms of ring B.

In some embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,(a substituted or unsubstituted monocyclic or bicyclic cycloalkyl), (asubstituted or unsubstituted monocyclic or bicyclic heterocycloalkyl), asubstituted or unsubstituted aryl, or a substituted or unsubstitutedheteroaryl, C₁-C₆alkylene-R¹⁴, —C₁-C₆alkylene-O—R¹⁴,—C₁-C₆alkylene-NR¹⁰—R¹⁴; —C₁-C₆alkylene-C(═O)—R¹⁴,—C₁-C₆alkylene-C(═O)O—R¹⁴—, or —C₁-C₆alkylene-C(═O)NR¹⁰—R¹⁴; each R¹⁴ isindependently selected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, a substituted or unsubstituted cycloalkyl, a substitutedor unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl,a substituted or unsubstituted benzyl, or a substituted or unsubstitutedheteroaryl.

In some embodiments, Q is —C(═O)-Q¹. In one aspect, Q¹ is —OH or —OR¹⁵.

In some embodiments, Q¹ is —OH, —OR¹⁵, —NHSO₂R⁹, or —N(R¹⁰)₂. In otherembodiments, Q¹ is selected from —OH, or —OR¹⁵. In further embodiments,Q¹ is selected from —OH, —OCH₃, or —OCH₂ CH₃. In some embodiments, Q¹ is—OH. In some embodiments, R¹⁵ is H or C₁-C₆alkyl. In other embodimentsR¹⁵ is H.

In some embodiments, each R¹ is independently selected from H, F, andC₁-C₄alkyl;

In one aspect, each R⁶ is each independently selected from H, F, andC₁-C₄alkyl. In some embodiments, each R⁶ is each independently selectedfrom H, F, and —CH₃. In some embodiments, each R⁶ is H.

In some embodiments, each R⁶ is each independently selected from H, andC₁-C₄alkyl.

In some embodiments, Q¹ is —OH, —OCH₃, or —OCH₂CH₃;

In some embodiments, each R¹ is independently selected from H, F, andC₁-C₄alkyl.

In some embodiments, R⁵ is H; and

In some embodiments, each R⁶ is H.

In one aspect, the compound of Formula (I) has the structure of Formula(II):

wherein:

each of A¹, A², A³, and A⁴ is each independently selected from C(R^(B)),N and —N⁺(—O⁻)—, provided that one or two of A¹, A², A³, and A⁴ is N or—N⁺(—O⁻)—.

In one aspect, one or two of A¹, A², A³, and A⁴ is N or —N⁺(—O⁻)—,provided that only one of A¹, A², A³, and A⁴ is —N⁺(—O⁻)—.

In some embodiments, A³ is CR^(B).

In some embodiments, A¹ is N or —N⁺(—O⁻)—. In some embodiments, A⁴ is Nor —N⁺(—O⁻)—.

In some embodiments, A² is CH.

In some embodiments, each R^(B) is independently selected from H,halogen, —CN, —NO₂, —OH, —OR¹⁰, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹,—N(R¹⁰)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰,—N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NR¹⁰C(═O)N(R¹⁰)₂,—NR¹⁰C(═O)R⁹, —NR¹⁰—C₁-C₄alkyl-C(═O)R⁹, —NR¹⁰C(═O)OR⁹, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, and a substitutedor unsubstituted heteroaryl.

In some embodiments, A¹ is N, —N⁺(—O⁻)— or CH; A² is CH; A³ is CR^(B);and A⁴ is N, —N⁺(—O⁻)— or CH; provided that at least one of A¹ and A⁴ isN or —N⁺(—O⁻)—.

In one aspect, A¹ is CH. In another aspect, A⁴ is CH.

In some embodiments, at least one of A¹ and A² is CH. In otherembodiments, A¹ and A² are CH. In some embodiments A¹ and A⁴ are N or—N⁺(—O⁻)—. In other embodiments, A² and A⁴ are N or —N⁺(—O⁻)—.

In some embodiments, X is a bond, —CH₂— or —O—. In further embodiments,X is a bond.

In some embodiments, each R^(B) is independently selected from H,halogen, —CN, —NO₂, —OH, —OR¹⁰, —S(═O)₂R⁹, —NHS(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,—C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,—OC(═O)N(R¹⁰)₂, —NHC(═O)N(R¹⁰)₂, —NHC(═O)R⁹, —NH—C₁-C₄alkyl-C(═O)R⁹,—NHC(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,C₁-C₆alkoxy, C₁-C₆heteroalkyl, a substituted or unsubstitutedcycloalkyl, a substituted or unsubstituted heterocycloalkyl, asubstituted or unsubstituted aryl, and a substituted or unsubstitutedheteroaryl.

In some other embodiments, each R^(B) is independently selected from H,halogen, —CN, —NO₂, —OH, —OR¹⁰, —S(═O)₂R⁹, —NHS(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,—CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NHC(═O)N(R¹⁰)₂, —NHC(═O)R⁹,—NH—C₁-C₄alkyl-C(═O)R⁹, —NHC(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, a substituted orunsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, and a substitutedor unsubstituted heteroaryl.

In some embodiments, the compound of Formula (II) has the followingstructure of Formula (IV):

In one aspect, the compound of Formula (I) has the structure of Formula(III):

wherein:

each of A⁵ and A⁶ is each independently selected from C—R^(B), N and—N⁺(—O⁻)—, provided that at least one of A⁵ or A⁶ is N or —N⁺(—O⁻)—.

In one aspect, at least one of A⁵ or A⁶ is N or —N⁺(—O⁻)— provided thatboth A⁵ and A⁶ are not —N⁺( O⁻)— at the same time.

In some embodiments, A⁵ is N or —N⁺(—O⁻)—. In some embodiments, A⁶ is Nor —N⁺(—O⁻)—.

In some embodiments, A⁵ is CH. In some embodiments, A⁶ is CH.

In some embodiments, each R^(B) is independently selected from H,halogen, —CN, —NO₂, —OH, —OR¹⁰, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹,—N(R¹⁰)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰,—N(R¹⁰)₂, —NHCH₂CO₂R¹⁰, —OCH₂CO₂R¹⁰, —SCH₂CO₂R¹⁰, —C(═O)N(R¹⁰)₂,—OC(═O)N(R¹⁰)₂, —NR¹⁰C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹,—NR¹⁰—C₁-C₄alkyl-C(═O)R⁹, —NR¹⁰C(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl.

In some embodiments, each R^(B) is independently selected from H,halogen, —CN, —NO₂, —OH, —OR¹⁰, —S(═O)₂R⁹, —NHS(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,—C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, N(R¹⁰)₂, C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂,—NHC(═O)N(R¹⁰)₂, —NHC(═O)R⁹, —NHC(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl.

In some embodiments, each R^(B) is independently selected from H,halogen, —CN, —NO₂, —OH, —OR¹⁰, —N(R¹⁰)₂, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl.

In some embodiments, each R^(B) is independently selected from H,halogen, —CN, —OH, —OR¹⁰, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆fluoroalkoxy, and C₁-C₆alkoxy.

In some embodiments, at least two R^(B) are H. In some embodiments, atleast three R^(B) are H. In some embodiments, at least four R^(B) are H.

In some embodiments, X is a bond.

In one aspect, each R¹ is independently selected from H, F, orC₁-C₄alkyl; or both R¹ groups are taken together with the carbon atom towhich they are attached form a cyclopropyl, cyclobutyl, cyclophenyl, orcyclohexyl. In some embodiments, each R¹ is independently selected fromH, F, and —CH₃. In one aspect, each R¹ is H.

In some embodiments, R¹⁵ is H.

In some embodiments, each of R², R³, and R⁴ is each independently H,halogen, —CN, —OH, —OR¹⁰, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, or C₁-C₆heteroalkyl.

In some embodiments, each of R², R³, and R⁴ is each independently H,halogen, CN, —OH, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆alkoxy, orC₁-C₆fluoroalkoxy.

In some embodiments, at least one of R², R³, and R⁴ is H. In someembodiments, at least two of R², R³, and R⁴ is H.

In some embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,(a substituted or unsubstituted monocyclic or bicyclic cycloalkyl), asubstituted or unsubstituted aryl, a substituted or unsubstitutedheteroaryl, C₁-C₆alkylene-R¹⁴, or —C₁-C₆alkylene-O—R¹⁴; each R¹⁴ isselected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, a substituted orunsubstituted benzyl, and a substituted or unsubstituted heteroaryl.

In some embodiments, R⁷ is —C(═O)R¹¹, —C(═O)OR¹², or —C(═O)N(R¹³)₂;

In some embodiments, R⁷ is —C(═O)R¹¹

In some embodiments, R¹¹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₁₀cycloalkyl, asubstituted or unsubstituted aryl, a substituted or unsubstitutedheteroaryl, a substituted or unsubstituted —C₁-C₆alkyl-cycloalkyl, asubstituted or unsubstituted —C₁-C₆alkyl-aryl or a substituted orunsubstituted —C₁-C₆alkyl-heteroaryl.

In some embodiments, R¹¹ is a substituted or unsubstituted aryl, asubstituted or unsubstituted heteroaryl, a substituted or unsubstituted—C₁-C₆alkyl-aryl or a substituted or unsubstituted—C₁-C₆alkyl-heteroaryl.

In some embodiments, R¹¹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, or a substituted or unsubstituted C₃-C₁₀cycloalkyl.

In some embodiments, R⁷ is —C(═O)OR¹². In some embodiments, R¹² isC₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted orunsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstituted aryl, asubstituted or unsubstituted heteroaryl, a substituted or unsubstituted—C₁-C₆alkyl-cycloalkyl, a substituted or unsubstituted —C₁-C₆alkyl-arylor a substituted or unsubstituted —C₁-C₆alkyl-heteroaryl.

In some embodiments, R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₁₀cycloalkyl, asubstituted or unsubstituted —C₁-C₆alkyl-cycloalkyl, a substituted orunsubstituted —C₁-C₆alkyl-aryl or a substituted or unsubstituted—C₁-C₆alkyl-heteroaryl.

In some embodiments, R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, or a substituted or unsubstituted C₃-C₁₀cycloalkyl.

In some embodiments, R⁷ is —C(═O)N(R¹³)₂. In some embodiments, each R¹³is independently H, —CN, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl,a substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted orunsubstituted aryl, a substituted or unsubstituted heteroaryl, asubstituted or unsubstituted —C₁-C₆alkyl-aryl or a substituted orunsubstituted —C₁-C₆alkyl-heteroaryl; or two R¹³ groups attached to thesame N atom are taken together with the N atom to which they areattached to form a substituted or unsubstituted heterocycloalkyl.

In some embodiments, each R¹³ is independently H, —CN, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or unsubstitutedC₃-C₁₀cycloalkyl, a substituted or unsubstituted aryl, a substituted orunsubstituted heteroaryl, a substituted or unsubstituted—C₁-C₆alkyl-aryl or a substituted or unsubstituted—C₁-C₆alkyl-heteroaryl.

In some embodiments, each R¹³ is independently H, —CN, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted—C₁-C₆alkyl-aryl or a substituted or unsubstituted—C₁-C₆alkyl-heteroaryl.

In some embodiments, each R¹³ is independently H, C₁-C₆alkyl,C₁-C₆fluoroalkyl, or C₁-C₆heteroalkyl.

In some embodiments, R⁷ is —S(═O)₂N(R¹³)₂ or —S(═O)₂R¹².

In some embodiments, R⁷ is —S(═O)₂R¹²; R¹² is C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted aryl,a substituted or unsubstituted heteroaryl.

In some embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl,(a substituted or unsubstituted monocyclic or bicyclic cycloalkyl) orC₁-C₆alkylene-R¹⁴; R¹⁴ is a substituted or unsubstituted aryl, or asubstituted or unsubstituted heteroaryl.

In some embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆heteroalkyl. In some embodiments, R⁸ is C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments, R⁸ is C₁-C₆alkylene-R¹⁴; R¹⁴ is a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl.

In some embodiments, the compound of Formula (III) has the followingstructure of Formula (V):

In one aspect, R¹ is as defined in Table 1. In one aspect, R², R³, R⁴are as defined in Table 1 and/or Table 2. In one aspect, R⁷ is asdefined in Table 1 and/or Table 2. In one aspect, R⁸ is as defined inTable 1 and/or Table 2. In one aspect, A¹ and A⁴ are as defined inTable 1. In one aspect, A⁵ and A⁶ are as defined in Table 2.

Any combination of the groups described above for the various variablesis contemplated herein.

In one aspect, compounds of Formula (I), Formula (II), Formula (III),Formula (IV) or Formula (V) include, but are not limited to, thosedescribed in Table 1:

TABLE 1

Cmpd # A¹ A⁴ R¹ R² R³ R⁴ R^(B) R⁸ R⁷ M + H* I-1 N CH H H H OCH₃ H HBenzyloxycarbonyl 407 I-2 N CH H H H OCH₃ —CH₃ —CH₂CH₃Cyclopropanecarbonyl 382 I-3 N CH H H H OCH₃ —CH₃ —CH₂CH₃3-Phenyl-propionyl 447 I-4 N CH H H H OCH₃ —CH₃ —CH₂CH₃ C(═O)NH-Benzyl447 I-5 CH N H H H OCH₃ —OCH₃ —CH₂CH₃ Cyclopropanecarbonyl 517 I-6 CH NH H H OCH₃ —OCH₃ —CH₂CH₃ C(O)NH-Benzyl 516 I-7 CH N H H H OCH₃ —OCH₃—CH₂CH₃ Acetyl 452 *mass spectrometric data

Compounds in Table 1 are named:

-   {3-[3-(Benzyloxycarbonylamino-methyl)-pyridin-2-yl]-4-methoxy-phenyl}-acetic    acid (Compound 1-1);    (3-{3-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-5-methyl-pyridin-2-yl}-4-methoxy-phenyl)-acetic    acid (Compound 1-2);    [3-(3-{[Ethyl-(3-phenyl-propionyl)-amino]-methyl}-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-acetic    acid (Compound 1-3);    {3-[3-(3-Benzyl-1-ethyl-ureidomethyl)-5-methyl-pyridin-2-yl]-4-methoxy-phenyl}-acetic    acid (Compound 1-4);    (3-{2-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-pyridin-3-yl}-4-methoxy-phenyl)-acetic    acid (Compound 1-5);    {3-[2-(3-Benzyl-1-ethyl-ureidomethyl)-6-methoxy-pyridin-3-yl]-4-methoxy-phenyl}-acetic    acid (Compound 1-6);    (3-{2-[(Acetyl-ethyl-amino)-methyl]-6-methoxy-pyridin-3-yl}-4-methoxy-phenyl)-acetic    acid (Compound 1-7).

TABLE 2

Cmpd # A⁵ A⁶ R¹ R² R³ R⁴ R⁸ R⁷ M + H* 2-1 N C H H H —OCH₃ —CH₂CH₃Cyclopropanecarbonyl 419 2-2 N C H H H —OCH₃ —CH₂CH₃ Acetyl 393 2-3 N CH H H —OCH₃ —CH₂CH₃ 2-Methoxy-acetyl 423 2-4 C N H H H —OCH₃ —CH₂CH₃Cyclopropanecarbonyl 419 2-5 C N H H H —OCH₃ —CH₂CH₃ Propionyl 407 2-6 CN H H H —OCH₃ —CH₂CH₃ 2-Methoxy-acetyl 423 2-7 C N H H H —OCH₃ BenzylAcetyl 455 2-8 C N H H H —OCH₃ Benzyl Cyclopropanecarbonyl 481 *massspectrometric data

Compounds in Table 2 are named:

-   (3-{3-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-acetic    acid (Compound 2-1);    (3-{3-[(Acetyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-acetic    acid (Compound 2-2);    [3-(3-{[Ethyl-(2-methoxy-acetyl)-amino]-methyl}-quinolin-2-yl)-4-methoxy-phenyl]-acetic    acid (Compound 2-3);    (3-{2-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-acetic    acid (Compound 2-4);    (3-{2-[(Ethyl-propionyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-acetic    acid (Compound 2-5);    3-(2-{[Ethyl-(2-methoxy-acetyl)-amino]-methyl}-quinolin-3-yl)-4-methoxy-phenyl]-acetic    acid (Compound 2-6);    (3-{2-[(Acetyl-benzyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-acetic    acid (Compound 2-7); and    (3-{2-[(Benzyl-cyclopropanecarbonyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-acetic    acid (Compound 2-8).

Synthesis of Compounds

Compounds of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) described in the prior section are synthesized usingstandard synthetic techniques or using methods known in the art incombination with methods described herein. In additions, solvents,temperatures and other reaction conditions presented herein may vary.

The starting material used for the synthesis of the compounds of Formula(I), Formula (II), Formula (III), Formula (IV) or Formula (V) describedin the prior section are either synthesized or obtained from commercialsources, such as, but not limited to, Aldrich Chemical Co. (Milwaukee,Wis.), or Sigma Chemical Co. (St. Louis, Mo.). The compounds describedherein, and other related compounds having different substituents aresynthesized using known techniques and materials, including those foundin March, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey andSundberg, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS3^(rd) Ed., (Wiley 1999). General methods for the preparation ofcompounds can be modified by the use of appropriate reagents andconditions for the introduction of the various moieties found in theformulae as provided herein.

In one aspect, compounds described herein are prepared according toScheme 1 (where R¹, R², R³, R⁴, R⁷, R⁸, R¹¹, R¹², R¹³, R^(B), A¹, A²,A⁵, A⁶ are as described herein).

Phenyl acetic acid esters of structure I are converted to boronic estersof structure II via metal-mediated reactions with boranes. Otherrelevant methods of borylation include, but not limited to, the Miyauraborylation reaction and other magnesium, lithium, copper, irridium andpalladium mediated reactions of triflates or halides with boranes (T.Ishiyama, et al., J. Org. Chem., 1995, 60, 7508-7510; X.-J. Wang, etal., Org. Lett., 2006, 8, 305-307; M. Murata, et al., Synlett, 2006,1867-1870; W. Zhu, D. Ma, Org. Lett., 2006, 8, 261-263). The aldehydemoiety of structure III is subjected to a reductive amination with anamine of HI structure IV to provide an amine of structure V. The amineof structure V is protected with an appropriate protecting group toprovide a compound of structure VI. The boronic acid moiety of structureII is coupled with the halide moiety of structure VI to provide acompound of structure VII. Other metal mediated coupling reactionsinclude reactions of boronic acids or esters with triflates or otherleaving groups, and include but are not limited to Suzuki reactions,Stille cross couplings, Negishi couplings, Kumada couplings, Ullmannreactions, Hiyama Coupling, and variants thereof (Metal-CatalyzedCross-Coupling Reactions, Armin de Meijere (Editor), François Diederich(Editor), John Wiley & Sons; 2nd edition, 2004; Özdemir, et al.,Tetrahedron, 2005, 61, 9791-9798; Ackermann, et al., Org. Lett., 2006,8, 3457-3460; Blakey, et al., J. Am. Chem. Soc., 2003, 125, 6046-6047;Dai, et al., Org. Lett., 2004, 6, 221-224; Yoshikai, et al, J. Am. Chem.Soc., 2005, 127, 17978-17979; Tang, et al, J. Org. Chem., 2006, 71,2167-2169; Murata, et al., Synthesis, 2001, 2231-2233).

The protected amino moiety of structure VII is deprotected to provide acompound of structure VIII. In some embodiments, amines of structureVIII are reacted with, but not limited to, a carboxylic acid andcoupling reagent such as EDC EDC, DCC, BOP, HATU or the like, or acarboxylic acid activated ester or an acid halide, alkylchloroformate,arylchloroformate, benzylchloroformate, alkylisocyanate,benzylisocyanate, arylisocyanate, alkylsulfonyl chloride, arylsulfonylchloride, heteroarylsulfonyl chloride, or the like in dichloromethane,dichloroethane, tetrahydrofuran, dimethoxyethane or the like in thepresence of a hindered base such as triethylamine,diisopropylethylamine, N-methylmorpholine, pyridine or the like, toprovide compounds of structure IX. Hydrolysis of the ester group ofcompounds of structure IX affords compounds of Formula (I).

In one aspect, amides are prepared as outlined in Scheme 2:

Reaction of amines of structure VIII with acid chlorides provides amidesof structure 2-I, which after hydrolysis of the ester moiety, affordcompounds of Formula (I).

In one aspect, carbamates are prepared as outlined in Scheme 3:

Reaction of amines of structure VIII with chloroformates providescarbamates of structure XII, which after hydrolysis of the ester moiety,afford compounds of Formula (I). Methods for the preparation ofcarbamates are known, such as described herein or in reference textssuch as, but not limited to, Greene, T. W. and Wuts, P. G. M “ProtectiveGroups in Organic Synthesis”, 3rd Edition, p. 549, New York: Wiley,1999. In one aspect, alkylamines (compounds of structure VIII) aretreated with phosgene or a phosgene equivalent, such as, for example,trichloromethyl chloroformate or carbonyldiimidazole, to yield anintermediate, which is then treated with a hydroxy containing compoundR¹²—OH to provide carbamates of structure XII.

In one aspect, sulfonamides of structure XIV are prepared as depicted inScheme 4:

Reaction of amines of structure VIII with sulfonyl chlorides providessulfonamides of structure XIV. Hydrolysis of ester group of compounds ofstructure XIV affords compounds of Formula (I).

In one aspect, ureas of structure XVI are prepared as depicted in Scheme5:

Reaction of amines of structure VIII with isocyanates of structure XVprovides ureas. Hydrolysis of ester group of compounds of structure XVIaffords compounds of Formula (I).

In one aspect, compounds described herein are prepared according toScheme 6.

Reduction of a nitrile of structure XVII provides an amine of structureXVIII. The amine of structure XVIII is reacted with a halide of formulaR⁷—Cl and then a halide of formula R⁸—Cl to provide a compound ofstructure X. Alternatively, the amine of structure XVIII is reacted witha halide of formula R⁷—Cl and then a halide of formula R⁸—Cl to providea compound of structure X.

In another aspect, compounds described herein are prepared according toScheme 7.

Phenyl acetic acid esters of structure I are converted to boronic estersof structure II via palladium metal-mediated reactions with boranes.Other methods of borylation are known. The aldehyde moiety of structureXIX is subjected to a reductive amination with an amine of structure XXto provide an amine of structure XXI. The amine of structure XXI isprotected with an appropriate protecting group to provide a compound ofstructure XXII. The boronic acid moiety of structure XVIII is coupledwith the halide moiety of structure XXII via a palladium mediatedreaction to provide a compound of structure XXIX. Other metal mediatedcoupling reactions are known.

The protected amino moiety of structure XXIX is deprotected to provide acompound of structure XXX. In some embodiments, amines of structure XXXare reacted with, but not limited to, a carboxylic acid and couplingreagent such as EDC EDC, DCC, BOP, HATU or the like, or a carboxylicacid activated ester or an acid halide, alkylchloroformate,arylchloroformate, benzylchloroformate, alkylisocyanate,benzylisocyanate, arylisocyanate, alkylsulfonyl chloride, arylsulfonylchloride, heteroarylsulfonyl chloride, or the like in dichloromethane,dichloroethane, tetrahydrofuran, dimethoxyethane or the like in thepresence of a hindered base such as triethylamine,diisopropylethylamine, N-methylmorpholine, pyridine or the like, toprovide compounds of structure XXXI. Hydrolysis of the ester group ofcompounds of structure XXXI affords compounds of Formula (I).

In one aspect, amides of structure XXIII are prepared as outlined inScheme 8:

Reaction of amines of structure XXX with acid chlorides provides amidesof structure XXXIII, which after hydrolysis of the ester moiety, affordcompounds of Formula (I).

In one aspect, carbamates of structure XXIV are prepared as outlined inScheme 9:

Reaction of amines of structure XXX with chloroformates providescarbamates of structure XXXIV, which after hydrolysis of the estermoiety, afford compounds of Formula (I).

In one aspect, sulfonamides of structure XXXV are prepared as depictedin Scheme 10:

Reaction of amines of structure XXX with sulfonyl chlorides providessulfonamides that are then treated with LiOH to provide sulfonamides ofstructure XXXV. Hydrolysis of to ester group of compounds of structureXXXV affords compounds of Formula I.

In one aspect, ureas of structure XXXVI are prepared as depicted inScheme 11:

Reaction of amines of structure XXX with isocyanates of structure XVprovides ureas. Hydrolysis of ester group of compounds of structure XXXVaffords compounds of Formula (I).

In one aspect, compounds of Formula (I), Formula (II), Formula (III),Formula (IV) or Formula (V) are synthesized as outlined in the Examples.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

In certain embodiments, the compounds described herein are modifiedusing various electrophiles or nucleophiles to form new functionalgroups or substituents. Table 3 entitled “Examples of Covalent Linkagesand Precursors Thereof” lists selected, non-limiting examples ofcovalent linkages and precursor functional groups that are used toprepare the modified compounds. Precursor functional groups are shown aselectrophilic groups and nucleophilic groups.

TABLE 3 Examples of Covalent Linkages and Precursors Thereof CovalentLinkage Product Electrophile Nucleophile Carboxamides Activated estersamines/anilines Carboxamides acyl azides amines/anilines Carboxamidesacyl halides amines/anilines Esters acyl halides alcohols/phenols Estersacyl nitriles alcohols/phenols Carboxamides acyl nitrilesamines/anilines Imines Aldehydes amines/anilines Hydrazones aldehydes orketones Hydrazines Oximes aldehydes or ketones Hydroxylamines Alkylamines alkyl halides amines/anilines Esters alkyl halides carboxylicacids Thioethers alkyl halides Thiols Ethers alkyl halidesalcohols/phenols Thioethers alkyl sulfonates Thiols Esters alkylsulfonates carboxylic acids Ethers alkyl sulfonates alcohols/phenolsEsters Anhydrides alcohols/phenols Carboxamides Anhydridesamines/anilines Thiophenols aryl halides Thiols Aryl amines aryl halidesAmines Thioethers Azindines Thiols Boronate esters Boronates GlycolsCarboxamides carboxylic acids amines/anilines Esters carboxylic acidsAlcohols hydrazines Hydrazides carboxylic acids N-acylureas orAnhydrides carbodiimides carboxylic acids Esters diazoalkanes carboxylicacids Thioethers Epoxides Thiols Thioethers haloacetamides ThiolsAmmotriazines halotriazines amines/anilines Triazinyl ethershalotriazines alcohols/phenols Amidines imido esters amines/anilinesUreas Isocyanates amines/anilines Urethanes Isocyanates alcohols/phenolsThioureas isothiocyanates amines/anilines Thioethers Maleimides ThiolsPhosphite esters phosphoramidites Alcohols Silyl ethers silyl halidesAlcohols Alkyl amines sulfonate esters amines/anilines Thioetherssulfonate esters Thiols Esters sulfonate esters carboxylic acids Etherssulfonate esters Alcohols Sulfonamides sulfonyl halides amines/anilinesSulfonate esters sulfonyl halides phenols/alcohols

Use of Protecting Groups

In the reactions described, it is necessary in certain embodiments toprotect reactive functional groups, for example hydroxy, amino, thiol orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Protecting groups areused to block some or all reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. In one embodiment, each protective group is removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval. In some embodiments, protective groups are removed by acid,base, and/or hydrogenolysis. Groups such as trityl, dimethoxytrityl,acetal and t-butyldimethylsilyl are acid labile and are used in certainembodiments to protect carboxy and hydroxy reactive moieties in thepresence of amino groups protected with Cbz groups, which are removableby hydrogenolysis, and/or Fmoc groups, which are base labile. In otherembodiments, carboxylic acid and hydroxy reactive moieties are blockedwith base labile groups such as, but not limited to, methyl, ethyl, andacetyl in the presence of amines blocked with acid labile groups such ast-butyl carbamate or with carbamates that are both acid and base stablebut hydrolytically removable.

In another embodiment, carboxylic acid and hydroxy reactive moieties areblocked with hydrolytically removable protective groups such as thebenzyl group, while amine groups capable of hydrogen bonding with acidsare blocked with base labile groups such as Fmoc. In another embodiment,carboxylic acid reactive moieties are protected by conversion to simpleester compounds as exemplified herein, or they are, in yet anotherembodiment, blocked with oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups are blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in the presence of acid- andbase-protecting groups since the former are stable and are optionallysubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid is optionally deprotected with aPd(0)-catalyzed reaction in the presence of acid labile t-butylcarbamate or base-labile acetate amine protecting groups. Yet anotherform of protecting group is a resin to which a compound or intermediateis attached. As long as the residue is attached to the resin, thatfunctional group is blocked and cannot react. Once released from theresin, the functional group is available to react.

Typically blocking/protecting groups are, by way of example only:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure.

Further Forms of Compounds

In certain embodiments, compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are prepared as a pharmaceuticallyacceptable acid addition salt (which is a type of a pharmaceuticallyacceptable salt) by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, including, butnot limited to, inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid,and the like; and organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroaceticacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid,ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, and muconic acid. In certain embodiments, compoundsof Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V)are prepared as N-oxides.

By “pharmaceutically acceptable,” as used herein, refers a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, pharmaceuticallyacceptable salts are obtained by reacting a compound of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V) with acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Pharmaceuticallyacceptable salts are also obtained by reacting a compound of Formula(I), Formula (II), Formula (III), Formula (IV) or Formula (V) with abase to form a salt such as an ammonium salt, an alkali metal salt, suchas a sodium or a potassium salt, an alkaline earth metal salt, such as acalcium or a magnesium salt, a salt of organic bases such asdicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,and salts with amino acids such as arginine, lysine, and the like.

In other embodiments, compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are prepared as a pharmaceuticallyacceptable salts by reacting the free acid form of the compound with apharmaceutically acceptable inorganic or organic base, including, butnot limited to organic bases such as ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, and the like, or withan inorganic base such as aluminum hydroxide, calcium hydroxide,potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and areoptionally formed during the process of crystallization withpharmaceutically acceptable solvents such as water, ethanol, and thelike. Hydrates are formed when the solvent is water, or alcoholates areformed when the solvent is alcohol. Solvates of compounds of Formula(I), Formula (II), Formula (III), Formula (IV) or Formula (V) areconveniently prepared or formed during the processes described herein.By way of example only, hydrates of compounds of Formula (I), Formula(II), Formula (III), Formula (IV) or Formula (V) are convenientlyprepared by recrystallization from an aqueous/organic solvent mixture,using organic solvents including, but not limited to, dioxane,tetrahydrofuran, ethanol, or methanol. In addition, certain compoundsprovided herein exist in unsolvated as well as solvated forms. Ingeneral, the solvated forms are considered equivalent to the unsolvatedforms for the purposes of the compounds and methods provided herein.

In yet other embodiments, the compounds of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) are prepared in variousforms, including but not limited to, amorphous forms, milled forms andnano-particulate forms. In addition, compounds of Formula (I), Formula(II), Formula (III), Formula (IV) or Formula (V) include crystallineforms, also known as polymorphs. Polymorphs include the differentcrystal packing arrangements of the same elemental composition of acompound. Polymorphs usually have different X-ray diffraction patterns,infrared spectra, melting points, density, hardness, crystal shape,optical and electrical properties, stability, and solubility. Variousfactors such as the recrystallization solvent, rate of crystallization,and storage temperature may cause a single crystal form to dominate.

In some embodiments, compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are prepared as prodrugs. A “prodrug”refers to an agent that is converted into the parent drug in vivo.Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. An example, without limitation, of a prodrug wouldbe a compound of Formula (I), Formula (II), Formula (III), Formula (IV)or Formula (V) which is administered as an ester (the “prodrug”) tofacilitate transmittal across a cell membrane where water solubility isdetrimental to mobility but which then is metabolically hydrolyzed tothe carboxylic acid, the active entity, once inside the cell wherewater-solubility is beneficial. A further example of a prodrug might bea short peptide (polyaminoacid) bonded to an acid group where thepeptide is metabolized to reveal the active moiety.

Prodrugs are generally drug precursors that, following administration toa subject and subsequent absorption, are converted to an active, or amore active species via some process, such as conversion by a metabolicpathway. Some prodrugs have a chemical group present on the prodrug thatrenders it less active and/or confers solubility or some other propertyto the drug. Once the chemical group has been cleaved and/or modifiedfrom the prodrug the active drug is generated. Prodrugs are often usefulbecause, in some situations, they are easier to administer than theparent drug. In certain embodiments, the prodrug of a compound describedherein is bioavailable by oral administration whereas the parent is not.Furthermore, in some embodiments, the prodrug of a compound describedherein has improved solubility in pharmaceutical compositions over theparent drug.

In other embodiments, prodrugs are designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. In specific embodiments, the design of prodrugsto date is to increase the effective water solubility of the therapeuticcompound for targeting to regions where water is the principal solvent.Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al.,Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom.,6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37,87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988);Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V.Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S.Symposium Series; and Edward B. Roche, Bioreversible Carriers in DrugDesign, American Pharmaceutical Association and Pergamon Press, 1987.

Additionally, prodrug derivatives of compounds of Formula (I), Formula(II), Formula (III), Formula (IV) or Formula (V) are prepared, ifdesired (e.g., for further details see Saulnier et al., (1994),Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). By way ofexample only, in one aspect appropriate prodrugs are prepared byreacting a non-derivatized compound of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) with a suitable carbamylatingagent, such as, but not limited to, 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like. Prodrug forms of the hereindescribed compounds, wherein the prodrug is metabolized in vivo toproduce a derivative as set forth herein are included within the scopeof the claims. Indeed, some of the herein-described compounds are aprodrug for another derivative or active compound.

In some embodiments, sites on the aromatic ring portion of compounds ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V)are susceptible to various metabolic reactions Therefore incorporationof appropriate substituents on the aromatic ring structures will reduce,minimize or eliminate this metabolic pathway. In specific embodiments,the appropriate substituent to decrease or eliminate the susceptibilityof the aromatic ring to metabolic reactions is, by way of example only,a halogen, or an alkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

In yet another embodiment, the compounds of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) possess one or morestereocenters and each center exists independently in either the R or Sconfiguration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. In certain embodiments, compounds ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V)are prepared as their individual stereoisomers by reacting a racemicmixture of the compound with an optically active resolving agent to forma pair of diastereoisomeric compounds, separating the diastereomers andrecovering the optically pure enantiomers. In some embodiments,resolution of enantiomers is carried out using covalent diastereomericderivatives of the compounds described herein. In other embodiments,dissociable complexes are utilized (e.g., crystalline diastereomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubilities, reactivity, etc.) and are, inspecific embodiments, separated by taking advantage of thesedissimilarities. In these embodiments, the diastereomers are separatedby chiral chromatography or by separation/resolution techniques basedupon differences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatdoes not result in racemization. Jean Jacques, Andre Collet, Samuel H.Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons,Inc., 1981.

Additionally, in certain embodiments, the compounds provided hereinexist as geometric isomers. The compounds and methods provided hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof. In someembodiments, the compounds described herein exist as tautomers. Alltautomers are intended to be within the scope of the molecular formulasdescribed herein. In additional embodiments of the compounds and methodsprovided herein, mixtures of enantiomers and/or diastereoisomers,resulting from a single preparative step, combination, orinterconversion are envisioned.

Certain Terminology

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed. In this application, the use of “or” or “and”means “and/or” unless stated otherwise. Furthermore, use of the term“including” as well as other forms, such as “include”, “includes,” and“included,” is not limiting.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylmoiety may be a saturated alkyl group or the alkyl moiety may be anunsaturated alkyl group. The alkyl moiety, whether saturated orunsaturated, may be branched or straight chain.

The “alkyl” moiety may have 1 to 10 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupmay consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., upto and including 10 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group of the compounds described herein may bedesignated as “C₁-C₆ alkyl” or similar designations. By way of exampleonly, “C₁-C₆ alkyl” indicates that there are one, two, three, four,five, or six carbon atoms in the alkyl chain, i.e., the alkyl chain isselected from the group consisting of methyl, ethyl, propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groupsinclude, but are in no way limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tertiary butyl, pentyl, hexyl, allyl, but-2-enyl,but-3-enyl, and the like. In one aspect, an alkyl is a C₁-C₆ alkyl.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where xand y are selected from the group x=1, y=1 and x=2, y=0. In someembodiments, when x=2 and y=0, the alkyl groups taken together with thenitrogen atom to which they are attached form a cyclic ring system.

An “amide” is a chemical moiety with formula —C(═O)NHR or —NHC(═O)R,where R is selected from the group consisting of alkyl, cycloalkyl,aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic(bonded through a ring carbon). An amide may be an amino acid or apeptide molecule attached to a compound of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V), thereby forming a prodrug.Any amine, or carboxyl side chain on the compounds described herein isoptionally amidified, as desired. See, e.g., Greene and Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York,N.Y., 1999, is incorporated herein by reference for such disclosure.

The term “aromatic” refers to a planar ring having a delocalizedit-electron system containing 4n+2π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, ten, ormore than ten atoms. Aromatics are a substituted or unsubstituted. Theterm “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl)and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups(e.g., pyridine). The term includes monocyclic or fused-ring polycyclic(i.e., rings which share adjacent pairs of carbon atoms) groups.

The term “carbocyclic” refers to a ring or ring system where the atomsforming the backbone of the ring are all carbon atoms. The term thusdistinguishes carbocyclic from heterocyclic rings in which the ringbackbone contains at least one atom which is different from carbon.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings are formed byfive, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups are a substituted or unsubstituted. In one aspect, an aryl is aphenyl or a naphthalenyl. Depending on the structure, an aryl group canbe a monoradical or a diradical (i.e., an arylene group). In one aspect,an aryl is a C₆-C₁₀aryl.

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic,non-aromatic radical, wherein each of the atoms forming the ring (i.e.skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, orpartially unsaturated. Cycloalkyls may be fused with an aromatic ring,and the point of attachment is at a carbon that is not an aromatic ringcarbon atom. Cycloalkyl groups include groups having from 3 to 10 ringatoms. Illustrative examples of cycloalkyl groups include, but are notlimited to, the following moieties:

and the like. In some embodiments, cycloalkyl groups are selected fromamong cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. In some embodiments, bicyclic cycloalkyl groups are selectedfrom among indanyl, indenyl, and 1,2,3,4-tetrahydronaphthalenyl.Cycloalkyl groups may be substituted or unsubstituted. Depending on thestructure, a cycloalkyl group can be a monoradical or a diradical (i.e.,an cycloalkylene group, such as, but not limited to,cyclopropan-1,1-diyl, cyclobutan-1,1-diyl, cyclopentan-1,1-diyl,cyclohexan-1,1-diyl, cycloheptan-1,1-diyl, and the like).

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalicyclic (bondedthrough a ring carbon). Any hydroxy, or carboxyl side chain on thecompounds described herein is esterified, if desired. Examples ofprocedures and specific groups to make such esters are found in sourcessuch as Greene and Wuts, Protective Groups in Organic Synthesis, 3^(rd)Ed., John Wiley & Sons, New York, N.Y., 1999.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo.

The term “haloalkyl” refers to an alkyl group in which one or morehydrogen atoms are replaced by one or more halide atoms. In one aspect,a haloalkyl is a C₁-C₄haloalkyl.

The term “fluoroalkyl” refers to a alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is aC₁-C₄fluoroalkyl.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Inone aspect, a heteroalkyl is a C₁-C₆ heteroalkyl.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings (also known asheteroalicyclic groups) containing one to four heteroatoms in thering(s), where each heteroatom in the ring(s) is selected from O, S andN, wherein each heterocyclic group has from 4 to 10 atoms in its ringsystem, and with the proviso that the any ring does not contain twoadjacent O or S atoms. Non-aromatic heterocyclic groups (also known asheterocycloalkyls) include groups having only 3 atoms in their ringsystem, but aromatic heterocyclic groups must have at least 5 atoms intheir ring system. The heterocyclic groups include benzo-fused ringsystems. An example of a 3-membered heterocyclic group is aziridinyl. Anexample of a 4-membered heterocyclic group is azetidinyl. An example ofa 5-membered heterocyclic group is thiazolyl. An example of a 6-memberedheterocyclic group is pyridyl, and an example of a 10-memberedheterocyclic group is quinolinyl. Examples of non-aromatic heterocyclicgroups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are imidazolyl,pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl,isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, thiadiazolyl,furazanyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,isoindolyl, pteridinyl, purinyl, benzofurazanyl, benzothienyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, and furopyridinyl. The foregoing groups may beC-attached or N-attached where such is possible. For instance, a groupderived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole may beimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles may besubstituted with one or two oxo (═O) moieties, such as pyrrolidin-2-one.The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. In one aspect, a heteroaryl is a monocyclicor bicyclic heteroaryl. Illustrative examples of heteroaryl groupsinclude the following moieties:

and the like. Monocyclic heteroaryls include imidazolyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl,thiazolyl, isothiazolyl, oxazolyl, isothiazolyl, pyrrolyl, thiadiazolyl,furazanyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,and triazinyl. In one aspect, monocyclic heteroaryls include imidazolyl,pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, isoxazolyl, thiazolyl,isothiazolyl, oxazolyl, isothiazolyl, pyrrolyl, thiadiazolyl, furazanyl,and oxadiazolyl. In one aspect, monocyclic heteroaryls includepyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Bicyclicheteroaryls include quinolinyl, isoquinolinyl, quinazolinyl,quinoxazolinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl,benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzimidazolyl, pyridopyrimidinyl, pyrazolopyrimidinyl, azaindolyl,pyrazolopyridinyl, thiazolopyrimidinyl, thiazolopyridinyl,pyridothienyl, pyrimidiothienyl and pyrrolopyrimidinyl. In one aspect, aheteroaryl contains 0-4 N atoms. In one aspect, a heteroaryl contains0-3 N atoms. In another aspect, a heteroaryl contains 1-3 N atoms. Inanother aspect, a heteroaryl contains 0-4 N atoms, 0-10 atoms, and 0-1 Satoms. In some embodiments, a heteroaryl is a C₁-C₉ heteroaryl. In someembodiments, a heteroaryl is a C₁-C₅ heteroaryl. In some embodiments, aheteroaryl is a C₆-C₉ heteroaryl.

A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkylgroup that includes at least one heteroatom selected from nitrogen,oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl.Illustrative examples of heterocycloalkyl groups, also referred to asnon-aromatic heterocycles, include:

and the like. In some embodiments, the heterocycloalkyl is selected fromoxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, and indolinyl. The term heteroalicyclicalso includes all ring forms of the carbohydrates, including but notlimited to the monosaccharides, the disaccharides and theoligosaccharides. In one aspect, a heterocycloalkyl is aC₂-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is aC₄-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is aC₃-C₆heterocycloalkyl. In one aspect, a heterocycloalkyl contains 0-2 Natoms. In another aspect, a heterocycloalkyl contains 0-2 N atoms, 0-2 Oatoms or 0-1 S atoms.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure. In one aspect, when a group describedherein is a bond, the referenced group is absent thereby allowing a bondto be formed between the remaining identified groups.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical and/or chemicalproperties as a carboxylic acid moiety. In one aspect, a carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisoteres of acarboxylic acid include, but are not limited to,

and the like.

The term “membered ring” includes any cyclic structure. The term“membered” is meant to denote the number of skeletal atoms thatconstitute the ring. Thus, for example, cyclohexyl, pyridinyl, pyranyland thiopyranyl are 6-membered rings and cyclopentyl, pyrrolyl, furanyl,and thienyl are 5-membered rings.

A “sulfoxide” refers to a —S(═O)— group.

A “sulfonyl” refers to a —S(═O)₂— group.

The term “a substituted or unsubstituted” means that the referencedgroup may be optionally substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone,cyano, halo, carbonyl, thiocarbonyl, nitro, haloalkyl, fluoroalkyl, andamino, including mono- and di-substituted amino groups, and theprotected derivatives thereof. By way of example an optional substituentmay be halide, —CN, —NO₂, or L_(s)R_(s), wherein each L_(s) isindependently selected from a bond, —O—, —C(═O)—, —C(═O)O—, —S—,—S(═O)—, —S(═O)₂—, —NH—, —NHC(═O)—, —C(═O)NH—, S(═O)₂NH—, —NHS(═O)₂,—OC(═O)NH—, —NHC(═O)O—, or —(C₁-C₆ alkyl)-; and each R_(s) is selectedfrom H, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl,or heterocycloalkyl. The protecting groups that may form the protectivederivatives of the above substituents may be found in sources such asGreene and Wuts, above. In one aspect, optional substituents areselected from halogen, —CN, —NH₂, —OH, —N(CH₃)₂, alkyl, fluoroalkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy,aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide,alkylsulfone, and arylsulfone. In some embodiments, an optionalsubstituents is halogen, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂, alkyl,fluoroalkyl, heteroalkyl, alkoxy, —S-alkyl, or —S(═O)₂alkyl. In someembodiments, substituted groups are substituted with one or moresubstituents selected from halogen, —OH, —OC₁-C₄alkyl, C₁-C₄alkyl,C₁-C₄heteroalkyl, C₁-C₄fluoroalkyl and —OC₁-C₄fluoroalkyl. In yet otherembodiments, substituted groups are substituted with one or moresubstituents selected from F, Cl, Br, —OH, —OCH₃, —CH₃, and —CF₃. Insome embodiments, substituted groups are substituted with one or two ofthe preceding groups.

In certain embodiments, the compounds presented herein possess one ormore stereocenters and each center independently exists in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. Stereoisomers are obtained, if desired, bymethods such as, the separation of stereoisomers by chiralchromatographic columns.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),or pharmaceutically acceptable salts of compounds having the structureof Formula (I), Formula (II), Formula (III), Formula (IV) or Formula(V), as well as active metabolites of these compounds having the sametype of activity. In some situations, compounds may exist as tautomers.All tautomers are included within the scope of the compounds presentedherein. In specific embodiments, the compounds described herein exist insolvated forms with pharmaceutically acceptable solvents such as water,ethanol, and the like. In other embodiments, the compounds describedherein exist in unsolvated form.

Certain Pharmaceutical and Medical Terminology

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator,” as used herein, refers to a molecule thatinteracts with a target either directly or indirectly. The interactionsinclude, but are not limited to, the interactions of an agonist, partialagonist, an inverse agonist and antagonist. In one embodiment, amodulator is an antagonist.

The term “agonist,” as used herein, refers to a molecule such as acompound, a drug, an enzyme activator or a hormone modulator that bindsto a specific receptor and triggers a response in the cell. An agonistmimics the action of an endogenous ligand (such as prostaglandin,hormone or neurotransmitter) that binds to the same receptor.

The term “antagonist,” as used herein, refers to a molecule such as acompound, which diminishes, inhibits, or prevents the action of anothermolecule or the activity of a receptor site. Antagonists include, butare not limited to, competitive antagonists, non-competitiveantagonists, uncompetitive antagonists, partial agonists and inverseagonists.

Competitive antagonists reversibly bind to receptors at the same bindingsite (active site) as the endogenous ligand or agonist, but withoutactivating the receptor.

Non-competitive antagonists (also known as allosteric antagonists) bindto a distinctly separate binding site from the agonist, exerting theiraction to that receptor via the other binding site. Non-competitiveantagonists do not compete with agonists for binding. The boundantagonists may result in a decreased affinity of an agonist for thatreceptor, or alternatively may prevent conformational changes in thereceptor required for receptor activation after the agonist binds.

Uncompetitive antagonists differ from non-competitive antagonists inthat they require receptor activation by an agonist before they can bindto a separate allosteric binding site.

Partial agonists are defined as drugs which, at a given receptor, mightdiffer in the amplitude of the functional response that they elicitafter maximal receptor occupancy.

Although they are agonists, partial agonists can act as a competitiveantagonist if co-administered with a full agonist, as it competes withthe full agonist for receptor occupancy and producing a net decrease inthe receptor activation observed with the full agonist alone.

An inverse agonist can have effects similar to an antagonist, but causesa distinct set of downstream biological responses. Constitutively activereceptors which exhibit intrinsic or basal activity can have inverseagonists, which not only block the effects of binding agonists like aclassical antagonist, but inhibit the basal activity of the receptor.

The term “PGD₂-dependent”, as used herein, refers to conditions ordisorders that would not occur, or would not occur to the same extent,in the absence of PGD₂.

The term “PGD₂-mediated”, as used herein, refers to refers to conditionsor disorders that might occur in the absence of PGD₂ but can occur inthe presence of PGD₂.

The term “asthma” as used herein refers to any disorder of the lungscharacterized by variations in pulmonary gas flow associated with airwayconstriction of whatever cause (intrinsic, extrinsic, or both; allergicor non-allergic). The term asthma may be used with one or moreadjectives to indicate cause.

The term “rhinitis” as used herein refers to any disorder of the nose inwhich there is inflammation of the mucous lining of the nose by whatevercause (intrinsic, extrinsic or both; allergic or non-allergic).

The term “bone disease,’ as used herein, refers to a disease orcondition of the bone, including, but not limited to, inappropriate boneremodeling, loss or gain, osteopenia, osteomalacia, osteofibrosis, andPaget's disease.

The term “cardiovascular disease,” as used herein refers to diseasesaffecting the heart or blood vessels or both, including but not limitedto: arrhythmia (atrial or ventricular or both); atherosclerosis and itssequelae; angina; cardiac rhythm disturbances; myocardial ischemia;myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke;peripheral obstructive arteriopathy of a limb, an organ, or a tissue;reperfusion injury following ischemia of the brain, heart or other organor tissue; endotoxic, surgical, or traumatic shock; hypertension,valvular heart disease, heart failure, abnormal blood pressure; shock;vasoconstriction (including that associated with migraines); vascularabnormality, inflammation, insufficiency limited to a single organ ortissue.

The term “cancer,” as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary,pancreas or other endocrine organ (thyroid), prostate, skin (melanoma)or hematological tumors (such as the leukemias).

The term “carrier,” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The term “dermatological disorder,” as used herein refers to a skindisorder. Such dermatological disorders include, but are not limited to,proliferative or inflammatory disorders of the skin such as, atopicdermatitis, bullous disorders, collagenoses, contact dermatitis eczema,Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, urticaria.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case may be determinedusing techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The terms “fibrosis” or “fibrosing disorder,” as used herein, refers toconditions that follow acute or chronic inflammation and are associatedwith the abnormal accumulation of cells and/or collagen and include butare not limited to fibrosis of individual organs or tissues such as theheart, kidney, joints, lung, or skin, and includes such disorders asidiopathic pulmonary fibrosis and cryptogenic fibrosing alveolitis.

The term “iatrogenic” means a PGD₂-dependent or PGD₂-mediated condition,disorder, or disease created or worsened by medical or surgical therapy.

The term “inflammatory disorders” refers to those diseases or conditionsthat are characterized by one or more of the signs of pain, heat,redness, swelling, and loss of function (temporary or permanent).Inflammation takes many forms and includes, but is not limited to,inflammation that is one or more of the following: acute, adhesive,atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated,exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic,hypertrophic, interstitial, metastatic, necrotic, obliterative,parenchymatous, plastic, productive, proliferous, pseudomembranous,purulent, sclerosing, seroplastic, serous, simple, specific, subacute,suppurative, toxic, traumatic, and/or ulcerative. Inflammatory disordersfurther include, without being limited to those affecting the bloodvessels (polyarteritis, temporal arteritis); joints (arthritis:crystalline, osteo-, psoriatic, reactive, rheumatoid, Reiter's);gastrointestinal tract (colitis); skin (dermatitis); or multiple organsand tissues (systemic lupus erythematosus).

The term “immunological disorders” refers to those diseases orconditions that are characterized by inappropriate or deleteriousresponse to an endogenous or exogenous antigen that may result incellular dysfunction or destruction and consequently dysfunction ordestruction of an organ or tissue and which may or may not beaccompanied by signs or symptoms of inflammation.

The terms “kit” and “article of manufacture” are used as synonyms.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

The terms “neurogenerative disease” or “nervous system disorder,” asused herein, refers to conditions that alter the structure or functionof the brain, spinal cord or peripheral nervous system, including butnot limited to Alzheimer's Disease, cerebral edema, cerebral ischemia,multiple sclerosis, neuropathies, Parkinson's Disease, those found afterblunt or surgical trauma (including post-surgical cognitive dysfunctionand spinal cord or brain stem injury), as well as the neurologicalaspects of disorders such as degenerative disk disease and sciatica. Theacronym “CNS” refers to disorders of the central nervous system, i.e.,brain and spinal cord.

The terms “ocular disease” or “ophthalmic disease,” as used herein,refer to diseases which affect the eye or eyes and potentially thesurrounding tissues as well. Ocular or ophthalmic diseases include, butare not limited to, conjunctivitis, retinitis, scleritis, uveitis,allergic conjuctivitis, vernal conjunctivitis, pappillaryconjunctivitis.

The term “interstitial cystitis” refers to a disorder characterized bylower abdominal discomfort, frequent and sometimes painful urinationthat is not caused by anatomical abnormalites, infection, toxins, traumaor tumors.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) and a co-agent, are both administeredto a patient simultaneously in the form of a single entity or dosage.The term “non-fixed combination” means that the active ingredients, e.g.a compound of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) and a co-agent, are administered to a patient as separateentities either simultaneously, concurrently or sequentially with nospecific intervening time limits, wherein such administration provideseffective levels of the two compounds in the body of the patient. Thelatter also applies to cocktail therapy, e.g. the administration ofthree or more active ingredients.

The term “pharmaceutical composition” refers to a mixture of a compoundof Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V)with other chemical components, such as carriers, stabilizers, diluents,dispersing agents, suspending agents, thickening agents, and/orexcipients. The pharmaceutical composition facilitates administration ofthe compound to an organism. Multiple techniques of administering acompound exist in the art including, but not limited to: intravenous,oral, aerosol, parenteral, ophthalmic, pulmonary and topicaladministration.

The term “respiratory disease,” as used herein, refers to diseasesaffecting the organs that are involved in breathing, such as the nose,throat, larynx, eustachian tubes, trachea, bronchi, lungs, relatedmuscles (e.g., diaphragm and intercostals) and nerves. Respiratorydiseases include, but are not limited to, asthma, adult respiratorydistress syndrome and allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitiveasthma, exercise-induced asthma, isocapnic hyperventilation, child-onsetasthma, adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis,perennial allergic rhinitis, chronic obstructive pulmonary disease,including chronic bronchitis or emphysema, pulmonary hypertension,interstitial lung fibrosis and/or airway inflammation and cysticfibrosis, and hypoxia.

The term “subject” or “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying causes of symptoms, inhibiting the disease or condition,e.g., arresting the development of the disease or condition, relievingthe disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Routes of Administration

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated withorgan-specific antibody. In such embodiments, the liposomes are targetedto and taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

Pharmaceutical Composition/Formulation

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. In specific embodiments, pharmaceuticalcompositions are formulated in a conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Any pharmaceuticallyacceptable techniques, carriers, and excipients are used as suitable toformulate the pharmaceutical compositions described herein: Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999).

Provided herein are pharmaceutical compositions comprising a compound ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V)and a pharmaceutically acceptable diluent(s), excipient(s), orcarrier(s). In certain embodiments, the compounds described areadministered as pharmaceutical compositions in which a compound ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V) ismixed with other active ingredients, as in combination therapy.Encompassed herein are all combinations of actives set forth in thecombination therapies section below and throughout this disclosure. Inspecific embodiments, the pharmaceutical compositions include one ormore compounds of Formula (I), Formula (II), Formula (III), Formula (IV)or Formula (V).

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. In certain embodiments, the pharmaceuticalcomposition facilitates administration of the compound to an organism.In some embodiments, practicing the methods of treatment or use providedherein, therapeutically effective amounts of compounds of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V) areadministered in a pharmaceutical composition to a mammal having adisease or condition to be treated. In specific embodiments, the mammalis a human. In certain embodiments, therapeutically effective amountsvary depending on the severity of the disease, the age and relativehealth of the subject, the potency of the compound used and otherfactors. The compounds described herein are used singly or incombination with one or more therapeutic agents as components ofmixtures.

In one embodiment, one or more compounds of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) is formulated in an aqueoussolutions. In specific embodiments, the aqueous solution is selectedfrom, by way of example only, a physiologically compatible buffer, suchas Hank's solution, Ringer's solution, or physiological saline buffer.In other embodiments, one or more compound of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) is formulated fortransmucosal administration. In specific embodiments, transmucosalformulations include penetrants that are appropriate to the barrier tobe permeated. In still other embodiments wherein the compounds describedherein are formulated for other parenteral injections, appropriateformulations include aqueous or nonaqueous solutions. In specificembodiments, such solutions include physiologically compatible buffersand/or excipients.

In another embodiment, compounds described herein are formulated fororal administration. Compounds described herein, including compounds ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V),are formulated by combining the active compounds with, e.g.,pharmaceutically acceptable carriers or excipients. In variousembodiments, the compounds described herein are formulated in oraldosage forms that include, by way of example only, tablets, powders,pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries,suspensions and the like.

In certain embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with one or more of thecompounds described herein, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as:for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Inspecific embodiments, disintegrating agents are optionally added.Disintegrating agents include, by way of example only, cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

In one embodiment, dosage forms, such as dragee cores and tablets, areprovided with one or more suitable coating. In specific embodiments,concentrated sugar solutions are used for coating the dosage form. Thesugar solutions, optionally contain additional components, such as byway of example only, gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dyestuffs and/orpigments are also optionally added to the coatings for identificationpurposes. Additionally, the dyestuffs and/or pigments are optionallyutilized to characterize different combinations of active compounddoses.

In certain embodiments, therapeutically effective amounts of at leastone of the compounds described herein are formulated into other oraldosage forms. Oral dosage forms include push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and aplasticizer, such as glycerol or sorbitol. In specific embodiments,push-fit capsules contain the active ingredients in admixture with oneor more filler. Fillers include, by way of example only, lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In other embodiments, softcapsules, contain one or more active compound that is dissolved orsuspended in a suitable liquid. Suitable liquids include, by way ofexample only, one or more fatty oil, liquid paraffin, or liquidpolyethylene glycol. In addition, stabilizers are optionally added.

In other embodiments, therapeutically effective amounts of at least oneof the compounds described herein are formulated for buccal orsublingual administration. Formulations suitable for buccal orsublingual administration include, by way of example only, tablets,lozenges, or gels. In still other embodiments, the compounds describedherein are formulated for parental injection, including formulationssuitable for bolus injection or continuous infusion. In specificembodiments, formulations for injection are presented in unit dosageform (e.g., in ampoules) or in multi-dose containers. Preservatives are,optionally, added to the injection formulations. In still otherembodiments, the pharmaceutical composition of Formula (I), Formula(II), Formula (III), Formula (IV) or Formula (V) are formulated in aform suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles. Parenteral injectionformulations optionally contain formulatory agents such as suspending,stabilizing and/or dispersing agents. In specific embodiments,pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form. Inadditional embodiments, suspensions of the active compounds are preparedas appropriate oily injection suspensions. Suitable lipophilic solventsor vehicles for use in the pharmaceutical compositions described hereininclude, by way of example only, fatty oils such as sesame oil, orsynthetic fatty acid esters, such as ethyl oleate or triglycerides, orliposomes. In certain specific embodiments, aqueous injectionsuspensions contain substances which increase the viscosity of thesuspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension contains suitable stabilizers oragents which increase the solubility of the compounds to allow for thepreparation of highly concentrated solutions. Alternatively, in otherembodiments, the active ingredient is in powder form for constitutionwith a suitable vehicle, e.g., sterile pyrogen-free water, before use.

In one aspect, compounds of Formula (I), Formula (II), Formula (III),Formula (IV) or Formula (V) are prepared as solutions for parenteralinjection as described herein or known in the art and administered withan automatic injector. Automatic injectors, such as those disclosed inU.S. Pat. Nos. 4,031,893, 5,358,489; 5,540,664; 5,665,071, 5,695,472 andWO/2005/087297 (each of which are incorporated herein by reference forsuch disclosure) are known. In general, all automatic injectors containa volume of solution that includes a compound of Formula (I), Formula(II), Formula (III), Formula (IV) or Formula (V) to be injected. Ingeneral, automatic injectors include a reservoir for holding thesolution, which is in fluid communication with a needle for deliveringthe drug, as well as a mechanism for automatically deploying the needle,inserting the needle into the patient and delivering the dose into thepatient. Exemplary injectors provide about 0.3 mL of solution at about aconcentration of 0.5 mg to 10 mg of compound of Formula (I), Formula(II), Formula (III), Formula (IV) or Formula (V) per 1 mL of solution.Each injector is capable of delivering only one dose of the compound.

In still other embodiments, the compounds of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) are administered topically.The compounds described herein are formulated into a variety oftopically administrable compositions, such as solutions, suspensions,lotions, gels, pastes, medicated sticks, balms, creams or ointments.Such pharmaceutical compositions optionally contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

In yet other embodiments, the compounds of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) are formulated fortransdermal administration. In specific embodiments, transdermalformulations employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Invarious embodiments, such patches are constructed for continuous,pulsatile, or on demand delivery of pharmaceutical agents. In additionalembodiments, the transdermal delivery of the compounds of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V) is accomplishedby means of iontophoretic patches and the like. In certain embodiments,transdermal patches provide controlled delivery of the compounds ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V).In specific embodiments, the rate of absorption is slowed by usingrate-controlling membranes or by trapping the compound within a polymermatrix or gel. In alternative embodiments, absorption enhancers are usedto increase absorption. Absorption enhancers or carriers includeabsorbable pharmaceutically acceptable solvents that assist passagethrough the skin. For example, in one embodiment, transdermal devicesare in the form of a bandage comprising a backing member, a reservoircontaining the compound optionally with carriers, optionally a ratecontrolling barrier to deliver the compound to the skin of the host at acontrolled and predetermined rate over a prolonged period of time, andmeans to secure the device to the skin.

Transdermal formulations described herein may be administered using avariety of devices which have been described in the art. For example,such devices include, but are not limited to, U.S. Pat. Nos. 3,598,122,3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636,3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084,4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303,5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and6,946,144.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. In one embodiment, the transdermal formulations described hereininclude at least three components: (1) a formulation of a compound ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V);(2) a penetration enhancer; and (3) an aqueous adjuvant. In addition,transdermal formulations can include additional components such as, butnot limited to, gelling agents, creams and ointment bases, and the like.In some embodiments, the transdermal formulation further include a wovenor non-woven backing material to enhance absorption and prevent theremoval of the transdermal formulation from the skin. In otherembodiments, the transdermal formulations described herein maintain asaturated or supersaturated state to promote diffusion into the skin.

In other embodiments, the compounds of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) are formulated foradministration by inhalation. Various forms suitable for administrationby inhalation include, but are not limited to, aerosols, mists orpowders. Pharmaceutical compositions of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) are conveniently delivered inthe form of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant (e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas). Inspecific embodiments, the dosage unit of a pressurized aerosol isdetermined by providing a valve to deliver a metered amount. In certainembodiments, capsules and cartridges of, such as, by way of exampleonly, gelatin for use in an inhaler or insufflator are formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Intranasal formulations are known in the art and are described in, forexample, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452, each ofwhich is specifically incorporated by reference. Formulations, whichinclude a compound of Formula (I), Formula (II), Formula (III), Formula(IV) or Formula (V), which are prepared according to these and othertechniques well-known in the art are prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, fluorocarbons,and/or other solubilizing or dispersing agents known in the art. See,for example, Ansel, H. C. et al., Pharmaceutical Dosage Forms and DrugDelivery Systems, Sixth Ed. (1995). Preferably these compositions andformulations are prepared with suitable nontoxic pharmaceuticallyacceptable ingredients. These ingredients are found in sources such asREMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005, astandard reference in the field. The choice of suitable carriers ishighly dependent upon the exact nature of the nasal dosage form desired,e.g., solutions, suspensions, ointments, or gels. Nasal dosage formsgenerally contain large amounts of water in addition to the activeingredient. Minor amounts of other ingredients such as pH adjusters,emulsifiers or dispersing agents, preservatives, surfactants, gellingagents, or buffering and other stabilizing and solubilizing agents mayalso be present. Preferably, the nasal dosage form should be isotonicwith nasal secretions.

For administration by inhalation, the compounds described herein, may bein a form as an aerosol, a mist or a powder. Pharmaceutical compositionsdescribed herein are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, such as, by way of example only, gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of the compound described herein and a suitable powder base such aslactose or starch.

In still other embodiments, the compounds of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) are formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

In certain embodiments, pharmaceutical compositions are formulated inany conventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Any pharmaceutically acceptable techniques,carriers, and excipients is optionally used as suitable and asunderstood in the art. Pharmaceutical compositions comprising a compoundof Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V)may be manufactured in a conventional manner, such as, by way of exampleonly, by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

Pharmaceutical compositions include at least one pharmaceuticallyacceptable carrier, diluent or excipient and at least one compound ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V)described herein as an active ingredient. The active ingredient is infree-acid or free-base form, or in a pharmaceutically acceptable saltform. In addition, the methods and pharmaceutical compositions describedherein include the use of N-oxides, crystalline forms (also known aspolymorphs), as well as active metabolites of these compounds having thesame type of activity. All tautomers of the compounds described hereinare included within the scope of the compounds presented herein.Additionally, the compounds described herein encompass unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. The solvated forms of the compoundspresented herein are also considered to be disclosed herein. Inaddition, the pharmaceutical compositions optionally include othermedicinal or pharmaceutical agents, carriers, adjuvants, such aspreserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure, buffers, and/orother therapeutically valuable substances.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The form of the pharmaceuticalcompositions described herein include liquid solutions or suspensions,solid forms suitable for solution or suspension in a liquid prior touse, or as emulsions. These compositions also optionally contain minoramounts of nontoxic, auxiliary substances, such as wetting oremulsifying agents, pH buffering agents, and so forth.

In some embodiments, pharmaceutical composition comprising at least onecompound of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) illustratively takes the form of a liquid where the agentsare present in solution, in suspension or both. Typically when thecomposition is administered as a solution or suspension a first portionof the agent is present in solution and a second portion of the agent ispresent in particulate form, in suspension in a liquid matrix. In someembodiments, a liquid composition includes a gel formulation. In otherembodiments, the liquid composition is aqueous.

In certain embodiments, pharmaceutical aqueous suspensions include oneor more polymers as suspending agents. Polymers include water-solublepolymers such as cellulosic polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linkedcarboxyl-containing polymers. Certain pharmaceutical compositionsdescribed herein include a mucoadhesive polymer, selected from, forexample, carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Pharmaceutical compositions also, optionally include solubilizing agentsto aid in the solubility of a compound of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V). The term “solubilizingagent” generally includes agents that result in formation of a micellarsolution or a true solution of the agent. Certain acceptable nonionicsurfactants, for example polysorbate 80, are useful as solubilizingagents, as can ophthalmically acceptable glycols, polyglycols, e.g.,polyethylene glycol 400, and glycol ethers.

Furthermore, pharmaceutical compositions optionally include one or morepH adjusting agents or buffering agents, including acids such as acetic,boric, citric, lactic, phosphoric and hydrochloric acids; bases such assodium hydroxide, sodium phosphate, sodium borate, sodium citrate,sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; andbuffers such as citrate/dextrose, sodium bicarbonate and ammoniumchloride. Such acids, bases and buffers are included in an amountrequired to maintain pH of the composition in an acceptable range.

Additionally, pharmaceutical compositions optionally include one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Other pharmaceutical compositions optionally include one or morepreservatives to inhibit microbial activity. Suitable preservativesinclude mercury-containing substances such as merfen and thiomersal;stabilized chlorine dioxide; and quaternary ammonium compounds such asbenzalkonium chloride, cetyltrimethylammonium bromide andcetylpyridinium chloride.

Still other pharmaceutical compositions include one or more surfactantsto enhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Still other pharmaceutical compositions may include one or moreantioxidants to enhance chemical stability where required. Suitableantioxidants include, by way of example only, ascorbic acid and sodiummetabisulfite.

In certain embodiments, pharmaceutical aqueous suspension compositionsare packaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers are used, in which case it istypical to include a preservative in the composition.

In alternative embodiments, other delivery systems for hydrophobicpharmaceutical compounds are employed. Liposomes and emulsions areexamples of delivery vehicles or carriers herein. In certainembodiments, organic solvents such as N-methylpyrrolidone are alsoemployed. In additional embodiments, the compounds described herein aredelivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials are useful herein. In someembodiments, sustained-release capsules release the compounds for a fewhours up to over 24 hours. Depending on the chemical nature and thebiological stability of the therapeutic reagent, additional strategiesfor protein stabilization may be employed.

In certain embodiments, the formulations described herein include one ormore antioxidants, metal chelating agents, thiol containing compoundsand/or other general stabilizing agents. Examples of such stabilizingagents, include, but are not limited to: (a) about 0.5% to about 2% w/vglycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% toabout 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/vpolysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l)pentosan polysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

Methods of Dosing and Treatment Regimens

In one embodiment, the compound of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) are used in the preparation ofmedicaments for the treatment of PGD₂-dependent or PGD₂-mediateddiseases or conditions. In addition, a method for treating any of thediseases or conditions described herein in a subject in need of suchtreatment, involves administration of pharmaceutical compositionscontaining at least one compound of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) or a pharmaceutically acceptablesalt, pharmaceutically active metabolite, pharmaceutically acceptableprodrug, or pharmaceutically acceptable solvate thereof, intherapeutically effective amounts to said subject.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest thesymptoms of the disease or condition. Amounts effective for this usedepend on the severity and course of the disease or condition, previoustherapy, the patient's health status, weight, and response to the drugs,and the judgment of the treating physician. Therapeutically effectiveamounts are optionally determined by methods including, but not limitedto, a dose escalation clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered may be temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Inspecific embodiments, the length of the drug holiday is between 2 daysand 1 year, including by way of example only, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days.The dose reduction during a drug holiday is, by way of example only, by10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but can nevertheless be determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated. In general, however, doses employed for adult humantreatment are typically in the range of 0.02 mg-5000 mg per day,preferably 1-1500 mg per day. In one embodiment, the desired dose isconveniently presented in a single dose or in divided doses administeredsimultaneously (or over a short period of time) or at appropriateintervals, for example as two, three, four or more sub-doses per day.

In some embodiments, compounds of Formula (I), Formula (II), Formula(III), Formula (IV), or Formula (V), are administered chronically. Insome embodiments, compounds of Formula (I), Formula (II), Formula (III),Formula (IV), or Formula (V), are administered intermittently (e.g. drugholiday that includes a period of time in which the compound is notadministered or is administered in a reduced amount). In someembodiments, compounds of Formula (I), Formula (II), Formula (III),Formula (IV), or Formula (V), are administered in cycles that include:(a) a first period that includes daily administration of the compound ofFormula (I), Formula (II), Formula (III), Formula (IV), or Formula (V);followed by (b) a second period that includes a dose reduction of thedaily amount of the compound of Formula (I), Formula (II), Formula(III), Formula (IV), or Formula (V), that is administered. In someembodiments, the compound of Formula (I), Formula (II), Formula (III),Formula (IV), or Formula (V) is not administered in the second period.In some embodiments, the duration of the first and second periods, aswell as the dose amounts are determined using methods described hereinor known in the art. By way of example only, a drug holiday or a dosereduction period is appropriate depending on the pharmacodynamic profileof the active agent, e.g., the ‘off’ rate of the active agent issignificantly slower than the ‘off’ rate of prostaglandin D₂ from theDP₂ receptor.

In certain embodiments, the pharmaceutical composition described hereinis in unit dosage forms suitable for single administration of precisedosages. In unit dosage form, the formulation is divided into unit dosescontaining appropriate quantities of one or more compound. In specificembodiments, the unit dosage is in the form of a package containingdiscrete quantities of the formulation. Non-limiting examples arepackaged tablets or capsules, and powders in vials or ampoules. Aqueoussuspension compositions are optionally packaged in single-dosenon-re-closeable containers. Alternatively, multiple-dose re-closeablecontainers are used, in which case it is typical to include apreservative in the composition. By way of example only, formulationsfor parenteral injection are, in some embodiments, presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

In one embodiment, the daily dosages appropriate for the compound ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V)described herein are from about 0.01 to about 10 mg/kg per body weight.In specific embodiments, an indicated daily dosage in a large mammal,including, but not limited to, humans, is in the range from about 0.5 mgto about 1000 mg, conveniently administered in divided doses, including,but not limited to, up to four times a day. In one embodiment, the dailydosage is administered in extended release form. In certain embodiments,suitable unit dosage forms for oral administration comprise from about 1to 500 mg active ingredient. In other embodiments, the daily dosage orthe amount of active in the dosage form are lower or higher than theranges indicated herein, based on a number of variables in regard to anindividual treatment regime. In various embodiments, the daily and unitdosages are altered depending on a number of variables including, butnot limited to, the activity of the compound used, the disease orcondition to be treated, the mode of administration, the requirements ofthe individual subject, the severity of the disease or condition beingtreated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit is expressed as the ratio between LD₅₀ and ED₅₀. In certainembodiments, the data obtained from cell culture assays and animalstudies are used in formulating the therapeutically effective dailydosage range and/or the therapeutically effective unit dosage amount foruse in mammals, including humans. In some embodiments, the daily dosageamount of the compounds described herein lies within a range ofcirculating concentrations that include the ED₅₀ with minimal toxicity.In certain embodiments, the daily dosage range and/or the unit dosageamount varies within this range depending upon the dosage form employedand the route of administration utilized.

Use of DP₂ Antagonists to Prevent and/or Treat PGD₂-Dependent or PGD₂Mediated Diseases or Conditions

The therapy of PGD₂-dependent or PGD₂-mediated diseases or conditions isdesigned to modulate the activity of DP₂, DP₁ and/or TP. Such modulationincludes, in some embodiments, antagonizing DP₂ activity. In otherembodiments, such modulation includes antagonizing DP₂ and DP₁. Forexample, in one embodiment, a DP₂ antagonist is administered in order todecrease signal transduction initiated by PGD₂ within the individual.

In accordance with one aspect, compositions and methods described hereininclude compositions and methods for treating, preventing, reversing,halting or slowing the progression of PGD₂-dependent or PGD₂ mediateddiseases or conditions once it becomes clinically evident, or treatingthe symptoms associated with or related to PGD₂-dependent or PGD₂mediated diseases or conditions, by administering to the subject acompound of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) or pharmaceutical composition or medicament thereof. Incertain embodiments, the subject already has a PGD₂-dependent or PGD₂mediated disease or condition at the time of administration, or is atrisk of developing a PGD₂-dependent or PGD₂ mediated disease orcondition.

In certain aspects, the activity of DP₂ in a mammal is directly orindirectly modulated by the administration of (at least once) aneffective amount of at least one compound of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) or pharmaceutical compositionor medicament thereof to a mammal Such modulation includes, but is notlimited to, reducing and/or inhibiting the activity of DP₂. Inadditional aspects, the activity of PGD₂ in a mammal is directly orindirectly modulated, including reducing and/or inhibiting, by theadministration of (at least once) an effective amount of at least onecompound of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) or pharmaceutical composition or medicament thereof to amammal Such modulation includes, but is not limited to, reducing and/orinhibiting the activity of DP₂.

In one embodiment, prevention and/or treatment of PGD₂-dependent or PGD₂mediated diseases or conditions comprises administering to a mammal atleast once a therapeutically effective amount of at least one compoundof Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V)or pharmaceutical composition or medicament thereof. In someembodiments, there is provided a method of treating PGD₂-dependent orPGD₂ mediated diseases or conditions that include, but are not limitedto, bone diseases and disorders, cardiovascular diseases and disorders,inflammatory diseases and disorders, immunological diseases ordisorders, dermatological diseases and disorders, ocular diseases anddisorders, cancer and other proliferative diseases and disorders,respiratory diseases and disorder, and non-cancerous disorders.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof at least one compound of Formula (I), Formula (II), Formula (III),Formula (IV) or Formula (V) or pharmaceutical composition or medicamentthereof. By way of example, in some embodiments, the respiratory diseaseis asthma. Other respiratory diseases include, but are not limited to,adult respiratory distress syndrome and allergic (extrinsic) asthma,non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma,clinical asthma, nocturnal asthma, allergen-induced asthma,aspirin-sensitive asthma, exercise-induced asthma, isocapnichyperventilation, child-onset asthma, adult-onset asthma, cough-variantasthma, occupational asthma, steroid-resistant asthma, seasonal asthma,allergic rhinitis, vascular responses, endotoxin shock, fibrogenesis,pulmonary fibrosis, allergic diseases, chronic inflammation, and adultrespiratory distress syndrome.

By way of example only, included in such treatment methods are methodsfor preventing chronic obstructive pulmonary disease comprisingadministering to the mammal at least once an effective amount of atleast one compound of Formula (I), Formula (II), Formula (III), Formula(IV) or Formula (V) or pharmaceutical composition or medicament thereof.In addition, chronic obstructive pulmonary disease includes, but is notlimited to, chronic bronchitis or emphysema, pulmonary hypertension,interstitial lung fibrosis and/or airway inflammation and cysticfibrosis.

By way of example only, included in such treatment methods are methodsfor preventing increased mucosal secretion and/or edema in a disease orcondition comprising administering to the mammal at least once aneffective amount of at least one compound of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) or pharmaceutical compositionor medicament thereof.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing or treatingvasoconstriction, atherosclerosis and its sequelae myocardial ischemia,myocardial infarction, aortic aneurysm, vasculitis and stroke comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I), Formula (II), Formula (III), Formula(IV) or Formula (V) or pharmaceutical composition or medicament thereof.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for reducing cardiac reperfusion injuryfollowing myocardial ischemia and/or endotoxic shock comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I), Formula (II), Formula (III), Formula(IV) or Formula (V) or pharmaceutical composition or medicament thereof.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for reducing the constriction of bloodvessels in a mammal comprising administering at least once to the mammalan effective amount of at least one compound of Formula (I), Formula(II), Formula (III), Formula (IV) or Formula (V) or pharmaceuticalcomposition or medicament thereof.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for lowering or preventing an increase inblood pressure of a mammal comprising administering at least once to themammal an effective amount of at least one compound of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V) orpharmaceutical composition or medicament thereof.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing or treating eosinophiland/or basophil and/or dendritic cell and/or neutrophil and/or monocyteand/or T-cell recruitment comprising administering at least once to themammal an effective amount of at least one compound of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V) orpharmaceutical composition or medicament thereof.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the prevention or treatment of abnormalbone remodeling, loss or gain, including diseases or conditions as, byway of example, osteopenia, osteoporosis, Paget's disease, cancer andother diseases comprising administering at least once to the mammal aneffective amount of at least one compound of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) or pharmaceutical compositionor medicament thereof.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing ocular inflammation andallergic conjunctivitis, vernal keratoconjunctivitis, and papillaryconjunctivitis comprising administering at least once to the mammal aneffective amount of at least one compound of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) or pharmaceutical compositionor medicament thereof.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing otitis, otitis mediacomprising administering at least once to the mammal an effective amountof at least one compound of Formula (I), Formula (II), Formula (III),Formula (IV) or Formula (V) or pharmaceutical composition or medicamentthereof.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing CNS disorders comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I), Formula (II), Formula (III), Formula(IV) or Formula (V) or pharmaceutical composition or medicament thereofCNS disorders include, but are not limited to, multiple sclerosis,Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia,retinal ischemia, post-surgical cognitive dysfunction, migraine, pain,peripheral neuropathy/neuropathic pain, spinal cord injury, cerebraledema and head injury.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of cancer comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I), Formula (II), Formula (III), Formula(IV) or Formula (V), or pharmaceutical composition or medicamentthereof. The type of cancer may include, but is not limited to,pancreatic cancer and other solid or hematological tumors.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing or reducing the chances ofendotoxic shock and septic shock comprising administering at least onceto the mammal an effective amount of at least one compound of Formula(I), Formula (II), Formula (III), Formula (IV) or Formula (V) orpharmaceutical composition or medicament thereof.

By way of example only, included in the prevention/treatment methodsdescribed herein methods for preventing, treating or alleviatingrheumatoid arthritis and osteoarthritis comprising administering atleast once to the mammal an effective amount of at least one compound ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V) orpharmaceutical composition or medicament thereof.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing increased, reducing theincidences of or treating gastrointestinal diseases comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I), Formula (II), Formula (III), Formula(IV) or Formula (V) or pharmaceutical composition or medicament thereof.Such gastrointestinal diseases include, by way of example only,inflammatory bowel disease (IBD), colitis and Crohn's disease.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the reduction or treatment ofinflammation and/or preventing, reducing the incidences of or treatingacute or chronic transplant rejection (including any vascularabnormality associated with acute or chronic rejection) or preventing ortreating tumors or accelerating the healing of wounds comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I), Formula (II), Formula (III), Formula(IV) or Formula (V) or pharmaceutical composition or medicament thereof.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the prevention or treatment ofrejection or dysfunction in a transplanted organ or tissue comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I), Formula (II), Formula (III), Formula(IV) or Formula (V) or pharmaceutical composition or medicament thereof.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for treating inflammatory responses of theskin comprising administering at least once to the mammal an effectiveamount of at least one compound of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) or pharmaceutical composition ormedicament thereof. Such inflammatory responses of the skin include, byway of example, psoriasis, dermatitis, contact dermatitis, eczema,urticaria, rosacea, wound healing and scarring. In another aspect aremethods for reducing psoriatic lesions in the skin, joints, or othertissues or organs, comprising administering at least once to the mammalan effective amount of at least one compound of Formula (I), Formula(II), Formula (III), Formula (IV) or Formula (V) or pharmaceuticalcomposition or medicament thereof.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of cystitis, including,e.g., interstitial cystitis, comprising administering at least once tothe mammal an effective amount of at least one compound of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V) orpharmaceutical composition or medicament thereof.

In one aspect, the compound of Formula (I), Formula (II), Formula (III),Formula (IV) or Formula (V) is used in the treatment of asthma,rhinitis, allergic conjuctivitis, atopic dermatitis, chronic obstructivepulmonary disease (COPD), pulmonary hypertension, interstitial lungfibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease,adult respiratory distress syndrome, myocardial infarction, aneurysm,stroke, cancer, wound healing, endotoxic shock, pain, inflammatoryconditions, eosinophilic esophagitis, eosinophil-associatedgastrointestinal disorders (EGID), idiopathic hypereosinophilicsyndrome, otitis, airway constriction, mucus secretion, nasalcongestion, increased microvascular permeability and recruitment ofeosinophils, urticaria, sinusitis, angioedema, anaphylaxia, chroniccough or Churg Strauss syndrome.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of Familial MediterraneanFever comprising administering at least once to the mammal an effectiveamount of at least one compound of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) or pharmaceutical composition ormedicament thereof.

Compounds of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) are DP₂ antagonists. In one aspect, compounds of Formula(I), Formula (II), Formula (III), Formula (IV) or Formula (V) are usedin the treatment of PGD₂-dependent or PGD₂-mediated diseases, disordersor conditions as disclosed herein. In some embodiments, the compounds ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V)show higher selectivity for DP₂ versus other receptors, such as forexample DP₁, CETP and/or PPAR receptors. In some embodiments, thecompounds of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) show higher affinity for DP₂ versus other receptors, such asfor example DP₁, CETP and/or PPAR receptors.

Combination Treatments

In certain instances, it is appropriate to administer at least onecompound of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) in combination with another therapeutic agent. By way ofexample only, if one of the side effects experienced by a patient uponreceiving one of the compounds herein is inflammation, then it may beappropriate to administer an anti-inflammatory agent in combination withthe initial therapeutic agent. Or, in one embodiment, the therapeuticeffectiveness of one of the compounds described herein is enhanced byadministration of an adjuvant (i.e., by itself the adjuvant may haveminimal therapeutic benefit, but in combination with another therapeuticagent, the overall therapeutic benefit to the patient is enhanced). Or,in some embodiments, the benefit of experienced by a patient isincreased by administering one of the compounds described herein withanother therapeutic agent (which also includes a therapeutic regimen)that also has therapeutic benefit. In one specific embodiment, thetherapeutic benefit of treating asthma by administering at least one ofthe compounds described herein is increased by also providing thepatient with other therapeutic agents or therapies for asthma. In anycase, regardless of the disease, disorder or condition being treated,the overall benefit experienced by the patient may simply be additive ofthe two therapeutic agents or the patient may experience a synergisticbenefit.

In certain embodiments, different therapeutically-effective dosages ofthe compounds disclosed herein will be utilized in formulatingpharmaceutical composition and/or in treatment regimens when thecompounds disclosed herein are administered in combination with one ormore additional agent, such as an additional therapeutically effectivedrug, an adjuvant or the like. Therapeutically-effective dosages ofdrugs and other agents for use in combination treatment regimens can bedetermined by means similar to those set forth hereinabove for theactives themselves. Furthermore, the methods of prevention/treatmentdescribed herein encompasses the use of metronomic dosing, i.e.,providing more frequent, lower doses in order to minimize toxic sideeffects. In some embodiments, a combination treatment regimenencompasses treatment regimens in which administration of a DP₂antagonist described herein is initiated prior to, during, or aftertreatment with a second agent described above, and continues until anytime during treatment with the second agent or after termination oftreatment with the second agent. It also includes treatments in which aDP₂ antagonist described herein and the second agent being used incombination are administered simultaneously or at different times and/orat decreasing or increasing intervals during the treatment period.Combination treatment further includes periodic treatments that startand stop at various times to assist with the clinical management of thepatient. For example, in one embodiment, a DP₂ antagonist describedherein in the combination treatment is administered weekly at the onsetof treatment, decreasing to biweekly, and decreasing further asappropriate.

Compositions and methods for combination therapy are provided herein. Inaccordance with one aspect, the pharmaceutical compositions disclosedherein are used to treat PGD₂-dependent or PGD₂ mediated conditions. Inaccordance with another aspect, the pharmaceutical compositionsdisclosed herein are used to treat respiratory diseases (e.g., asthma),where treatment with a DP₂ antagonist is indicated and to inducebronchodilation in a subject. In one embodiment, the pharmaceuticalcompositions disclosed herein are used to treat airways or nasalinflammation diseases such as asthma and rhinitis.

In one embodiment, pharmaceutical compositions disclosed herein are usedto treat a subject suffering from a vascular inflammation-drivendisorder. In one embodiment, the pharmaceutical compositions disclosedherein are used to treat skin inflammation diseases such as atopicdermatitis.

In certain embodiments, combination therapies described herein are usedas part of a specific treatment regimen intended to provide a beneficialeffect from the co-action of a DP₂ described herein and a concurrenttreatment. It is understood that the dosage regimen to treat, prevent,or ameliorate the condition(s) for which relief is sought, is modifiedin accordance with a variety of factors. These factors include the typeof respiratory disorder and the type of bronchoconstriction orinflammation from which the subject suffers, as well as the age, weight,sex, diet, and medical condition of the subject. Thus, in someinstances, the dosage regimen actually employed varies and, in someembodiments, deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more biologically active agents, thecompound provided herein is administered either simultaneously with thebiologically active agent(s), or sequentially. If administeredsequentially, the attending physician decides on the appropriatesequence of administering protein in combination with the biologicallyactive agent(s).

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills). In one embodiment, one of the therapeutic agents isgiven in multiple doses, and in another, two (or more if present) aregiven as multiple doses. In some embodiments of non-simultaneousadministration, the timing between the multiple doses vary from morethan zero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations is alsoenvisioned.

In additional embodiments, the compounds of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) are used in combination withprocedures that provide additional or synergistic benefit to thepatient. By way of example only, patients are expected to findtherapeutic and/or prophylactic benefit in the methods described herein,wherein pharmaceutical composition of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) and/or combinations with othertherapeutics are combined with genetic testing to determine whether thatindividual is a carrier of a mutant gene that is known to be correlatedwith certain diseases or conditions.

The compounds of Formula (I), Formula (II), Formula (III), Formula (IV)or Formula (V) and combination therapies are administered before, duringor after the occurrence of a disease or condition, and the timing ofadministering the composition containing a compound varies. Thus, in oneembodiment, the compounds described herein are used as a prophylacticand are administered continuously to subjects with a propensity todevelop conditions or diseases in order to prevent the occurrence of thedisease or condition. In another embodiment, the compounds andcompositions are administered to a subject during or as soon as possibleafter the onset of the symptoms. The administration of the compounds areinitiated within the first 48 hours of the onset of the symptoms,preferably within the first 48 hours of the onset of the symptoms, morepreferably within the first 6 hours of the onset of the symptoms, andmost preferably within 3 hours of the onset of the symptoms. The initialadministration is accomplished via any practical route, such as, forexample, by intravenous injection, a bolus injection, infusion over 5minutes to about 5 hours, a pill, a capsule, transdermal patch, buccaldelivery, and the like, or combination thereof. In specific embodiments,a compound described herein is administered as soon as is practicableafter the onset of a disease or condition is detected or suspected, andfor a length of time necessary for the treatment of the disease, suchas, for example, from about 1 month to about 3 months. In someembodiments, the length required for effective treatment varies, and thetreatment length is adjusted to suit the specific needs of each subject.For example, in specific embodiments, a compound described herein or aformulation containing the compound is administered for at least 2weeks, about 1 month to about 5 years, or from about 1 month to about 3years.

By way of example, therapies which combine compounds of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V) with inhibitorsof PGD₂ synthesis or PGD₂ receptor antagonists, either acting at thesame or other points in the PGD₂ synthesis pathway, are encompassedherein for treating PGD₂-dependent or PGD₂ mediated diseases orconditions. In addition, by way of example, encompassed herein aretherapies that combine compounds of Formula (I), Formula (II), Formula(III), Formula (IV) or Formula (V) with inhibitors of inflammation fortreating PGD₂-dependent or PGD₂ mediated diseases or conditions.

Anti-Inflammatory Agents

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases includeadministration to a patient compounds, pharmaceutical compositions, ormedicaments described herein in combination with an anti-inflammatoryagent including, but not limited to, non-steroidal anti-inflammatorydrugs (NSAIDs) and corticosteroids (glucocorticoids). Anti-inflammatoryagents include, but are not limited to: arthrotec, mesalamine,auralglan, sulfasalazine, daypro, etodolac, ponstan, and solumedrol;non-steroidal anti-inflammatory agents; corticosteroids; and leukotrienepathway modulators (e.g. montelukast, zilueton).

By way of example only, asthma is a chronic inflammatory diseasecharacterized by pulmonary eosinophilia and airway hyperresponsiveness.In patients with asthma, PGD₂ is released from mast cells, eosinophils,and basophils. PGD₂ is involved in contraction of airway smooth muscle,an increase in vascular permeability and mucus secretions, and has beenreported to attract and activate inflammatory cells in the airways ofasthmatics. Thus, in another embodiment described herein, the methodsfor treatment of respiratory diseases include administration to apatient compounds, pharmaceutical compositions, or medicaments describedherein in combination with an anti-inflammatory agent.

NSAIDs include, but are not limited to: aspirin, salicylic acid,gentisic acid, choline magnesium salicylate, choline salicylate, cholinemagnesium salicylate, choline salicylate, magnesium salicylate, sodiumsalicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium,fluorobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolactromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin,sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid,piroxicam, meloxicam, COX-2 specific inhibitors (such as, but notlimited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib,lumiracoxib, CS-502, JTE-522, L-745,337 and NS398).

Corticosteroids, include, but are not limited to: betamethasone(Celestone), prednisone (Deltasone), alclometasone, aldosterone,amcinonide, beclometasone, betamethasone, budesonide, ciclesonide,clobetasol, clobetasone, clocortolone, cloprednol, cortisone,cortivazol, deflazacort, deoxycorticosterone, desonide, desoximetasone,desoxycortone, dexamethasone, diflorasone, diflucortolone,difluprednate, fluclorolone, fludrocortisone, fludroxycortide,flumetasone, flunisolide, fluocinolone acetonide, fluocinonide,fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene,fluticasone, formocortal, halcinonide, halometasone,hydrocortisone/cortisol, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone butyrate, loteprednol, medrysone,meprednisone, methylprednisolone, methylprednisolone aceponate,mometasone furoate, paramethasone, prednicarbate,prednisone/prednisolone, rimexolone, tixocortol, triamcinolone, andulobetasol.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases includeadministration to a patient compounds, pharmaceutical compositions, ormedicaments described herein in combination in combination with NSAIDsand NO-donors or NSAIDs and proton-pump inhibitors.

PGD₂ Receptor Antagonists

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases includesadministering to a patient compounds, pharmaceutical compositions, ormedicaments described herein in combination with other PGD₂ receptorantagonists including, but are not limited to, DP₁ receptor antagonistsand TP receptor antagonists. In another embodiment described herein,methods for treatment of PGD₂-dependent or PGD₂ mediated conditions ordiseases includes administered to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination with a DP₁receptor antagonist. DP₁ receptor antagonists include, but are notlimited to, BWA868C (Sharif et al., Br. J. Pharmacol., 2000 November;131(6):1025-38), MK-0524 (Sturino et al, J. Med. Chem., 2007, 50,794-806 and Cheng et al, PNAS, 2006 Apr. 25; 103(17):6682-7.) and S-5751(Arimura et al., J. Pharmacol. Exp. Ther., 2001 August; 298(2):411-9).For some patients, the most appropriate formulation or method of use ofsuch combination treatments depends on the type of PGD₂-dependent orPGD₂ mediated disorder, the time period in which the DP₂ antagonist actsto treat the disorder and/or the time period in which the DP₁ receptorantagonist acts to prevent DP₁ receptor activity. By way of exampleonly, some embodiments described herein provide for such combinationtreatments that are used for treating a patient suffering fromrespiratory disorders such as asthma and rhinitis.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases includesadministering to a patient compounds, pharmaceutical compositions, ormedicaments described herein in combination with a TP receptorantagonist. TP receptor antagonists include, but are not limited to,Ramatroban (“Bayer™”), GR32191 (Beasley et al., J. Appl. Physiol., 1989April; 66(4):1685-93), IC1192605 (Boersma et al., Br. J. Pharmacol.,1999 December; 128(7):1505-12) and derivatives or analogs thereof. Suchcombinations may be used to treat PGD₂-dependent or PGD₂ mediateddisorders, including respiratory disorders.

In one embodiment, the co-administration of a DP₂ receptor antagonistwith a DP₁ receptor antagonist or a TP receptor antagonist hastherapeutic benefit over and above the benefit derived from theadministration of a either a DP₂ antagonist, DP₁ antagonist or a TPantagonist alone. In the case that substantial inhibition of PGD₂activity has undesired effects, partial inhibition of this pathwaythrough the amelioration of the effects of the proinflammatory agonistscombined with the block of the DP₁ receptor, TP receptor and/or DP₂receptor may afford substantial therapeutic benefits, particularly forrespiratory diseases.

Other Combination Therapies

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such asproliferative disorders, including cancer, comprises administration to apatient compounds, pharmaceutical compositions, or medicaments describedherein in combination with at least one additional agent selected, byway of example only, alemtuzumab, arsenic trioxide, asparaginase(pegylated or non-), bevacizumab, cetuximab, platinum-based compoundssuch as cisplatin, cladribine, daunorubicin/doxorubicin/idarubicin,irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate,Paclitaxel™, taxol, temozolomide, thioguanine, or classes of drugsincluding hormones (an antiestrogen, an antiandrogen, or gonadotropinreleasing hormone analogues, interferons such as alpha interferon,nitrogen mustards such as busulfan or melphalan or mechlorethamine,retinoids such as tretinoin, topoisomerase inhibitors such as irinotecanor topotecan, tyrosine kinase inhibitors such as gefinitinib orimatinib, or agents to treat signs or symptoms induced by such therapyincluding allopurinol, filgrastim, granisetron/ondansetron/palonosetron,dronabinol.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of transplanted organs or tissues or cells, comprisesadministration to a patient compounds, pharmaceutical compositions, ormedicaments described herein in combination with at least one additionalagent selected from, by way of example only, azathioprine, acorticosteroid, cyclophosphamide, cyclosporin, dacluzimab, mycophenolatemofetil, OKT3, rapamycin, tacrolimus, thymoglobulin.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such asatherosclerosis, comprises administration to a patient compounds,pharmaceutical compositions, or medicaments described herein incombination with at least one additional agent selected, by way ofexample only, HMG-CoA reductase inhibitors (e.g., statins in theirlactonized or dihydroxy open acid forms and pharmaceutically acceptablesalts and esters thereof, including but not limited to lovastatin;simvastatin; dihydroxy open-acid simvastatin, particularly the ammoniumor calcium salts thereof; pravastatin, particularly the sodium saltthereof; fluvastatin, particularly the sodium salt thereof;atorvastatin, particularly the calcium salt thereof; nisvastatin, alsoreferred to as NK-104; rosuvastatin); agents that have bothlipid-altering effects and other pharmaceutical activities; HMG-CoAsynthase inhibitors; cholesterol absorption inhibitors such asezetimibe; cholesterol ester transfer protein (CETP) inhibitors, forexample JTT-705 and CP529, 414; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors);acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT-1 and -2; microsomal triglyceride transfer protein (MTP)inhibitors; probucol; niacin; bile acid sequestrants; LDL (low densitylipoprotein) receptor inducers; platelet aggregation inhibitors, forexample glycoprotein IIb/IIIa fibrinogen receptor antagonists andaspirin; human peroxisome proliferator activated receptor gamma (PPARγ)agonists, including the compounds commonly referred to as glitazones,for example troglitazone, pioglitazone and rosiglitazone and includingthose compounds included within the structural class known asthiazolidinediones as well as those PPARγ agonists outside thethiazolidinedione structural class; PPARα agonists such as clofibrate,fenofibrate including micronized fenofibrate, and gemfibrozil; PPAR dualα/γ agonists such as5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide,known as KRP-297; vitamin B6 (also known as pyridoxine) and thepharmaceutically acceptable salts thereof such as the HCl salt; vitaminB12 (also known as cyanocobalamin); folic acid or a pharmaceuticallyacceptable salt or ester thereof such as the sodium salt and themethylglucamine salt; anti-oxidant vitamins such as vitamin C and E andbeta carotene; beta-blockers; angiotensin II antagonists such aslosartan; angiotensin converting enzyme inhibitors such as enalapril andcaptopril; calcium channel blockers such as nifedipine and diltiazam;endothelian antagonists; agents that enhance ABC1 gene expression; FXRand LXR ligands including both inhibitors and agonists; bisphosphonatecompounds such as alendronate sodium; and cyclooxygenase-2 inhibitorssuch as rofecoxib and celecoxib.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of stroke, comprises administration to a patient compounds,pharmaceutical compositions, or medicaments described herein incombination with at least one additional agent selected from, by way ofexample only, COX-2 inhibitors; nitric oxide synthase inhibitors, suchas N-(3-(aminomethyl)benzyl)acetamidine; Rho kinase inhibitors, such asfasudil; angiotension II type-1 receptor antagonists, includingcandesartan, losartan, irbesartan, eprosartan, telmisartan andvalsartan; glycogen synthase kinase 3 inhibitors; sodium or calciumchannel blockers, including crobenetine; p38 MAP kinase inhibitors,including SKB 239063; thromboxane AX-synthetase inhibitors, includingisbogrel, ozagrel, ridogrel and dazoxiben; statins (HMG CoA reductaseinhibitors), including lovastatin, simvastatin, dihydroxy open-acidsimvastatin, pravastatin, fluvastatin, atorvastatin, nisvastatin, androsuvastatin; neuroprotectants, including free radical scavengers,calcium channel blockers, excitatory amino acid antagonists, growthfactors, antioxidants, such as edaravone, vitamin C, TROLOX™, citicolineand minicycline, and reactive astrocyte inhibitors, such as(2R)-2-propyloctanoic acid; beta andrenergic blockers, such aspropranolol, nadolol, timolol, pindolol, labetalol, metoprolol,atenolol, esmolol and acebutolol; NMDA receptor antagonists, includingmemantine; NR2B antagonists, such as traxoprodil; 5-HT1A agonists;receptor platelet fibrinogen receptor antagonists, including tirofibanand lamifiban; thrombin inhibitors; antithrombotics, such as argatroban;antihypertensive agents, such as enalapril; vasodilators, such ascyclandelate; nociceptin antagonists; DPIV antagonists; GABA 5 inverseagonists; and selective androgen receptor modulators.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of pulmonary fibrosis, comprises administration to a patientcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from, by wayof example only, anti-inflammatory agents, such as corticosteroids,azathioprine or cyclophosphamide.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of interstitial cystitis, comprises administration to a patientcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from, by wayof example only, dimethylsulfoxide, omalizumab, and pentosanpolysulfate.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of disorders of bone, comprises administration to a patientcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from the, byway of example only, minerals, vitamins, bisphosphonates, anabolicsteroids, parathyroid hormone or analogs, and cathepsin K inhibitors.

In yet another embodiment described herein, methods for treatingPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of respiratory disorders (e.g., asthma, COPD and rhinitis),comprises administration to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination with atleast one agent used in the treatment of respiratory conditions. Agentsused in the treatment of respiratory conditions include, but are notlimited to, bronchodilators (e.g., sympathomimetic agents and xanthinederivatives), leukotriene receptor antagonists, leukotriene formationinhibitors, leukotriene modulators, nasal decongestants, respiratoryenzymes, lung surfactants, antihistamines (e.g., mepyramine(pyrilamine), antazoline, diphenhydramine, carbinoxamine, doxylamine,clemastine, dimenhydrinate, pheniramine, chlorphenamine(chlorpheniramine), dexchlorpheniramine, brompheniramine, triprolidine,cetirizine, cyclizine, chlorcyclizine, hydroxyzine, meclizine,loratadine, desloratidine, promethazine, alimemazine (trimeprazine),cyproheptadine, azatadine, ketotifen, acrivastine, astemizole,cetirizine, mizolastine, terfenadine, azelastine, levocabastine,olopatadine, levocetirizine, fexofenadine), mucolytics, corticosteroids,glucocorticoids, anticholinergics, antitussives, analgesics,expectorants, albuterol, ephedrine, epinephrine, fomoterol,metaproterenol, terbutaline, budesonide, ciclesonide, dexamethasone,flunisolide, fluticasone propionate, triamcinolone acetonide,ipratropium bromide, pseudoephedrine, theophylline, montelukast,zafirlukast, ambrisentan, bosentan, enrasentan, sitaxsentan, tezosentan,iloprost, treprostinil, pirfenidone, FLAP inhibitors, FLAP modulatorsand 5-LO inhibitors.

In a specific embodiment described herein, methods for treatingPGD₂-dependent or

PGD₂ mediated conditions or diseases, such as the therapy of asthmaand/or COPD, comprises administration to a patient anti-inflammatoryagents. In certain embodiments, methods for treating PGD₂-dependent orPGD₂ mediated conditions or diseases, such as the therapy of asthmaand/or COPD, comprise administration to a patient compounds,pharmaceutical compositions, or medicaments described herein incombination with at least one additional agent selected from, but notlimited to, epinephrine, isoproterenol, orciprenaline, bronchodilators,glucocorticoids, leukotriene modifiers, mast-cell stabilizers,xanthines, anticholinergics, β-2 agonists, FLAP inhibitors, FLAPmodulators or 5-LO inhibitors. β-2 agonists include, but are not limitedto, short-acting β-2 agonists (e.g., salbutamol (albuterol),levalbuterol, terbutaline, pirbuterol, procaterol, metaproterenol,fenoterol and bitolterol mesylate) and long-acting β-2 agonists (e.g.,salmeterol, formoterol, bambuterol and clenbuterol). FLAP inhibitorsand/or FLAP modulators include, but are not limited to,3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid,3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid, MK-886, MK-0591, BAY-x1005 and compounds found in US 2007/0225285,US 2007/0219206, US 2007/0173508, US 2007/0123522 and US 2007/0105866(each of which are hereby incorporated by reference). Glucocorticoidsinclude, but are not limited to, beclometasone, budesonide, ciclesonide,fluticasone and mometasone. Anticholinergics include, but are notlimited to, ipratropium and tiotropium. Mast cell stabilizers include,but are not limited to, cromoglicate and nedocromil. Xanthines include,but are not limited to, amminophylline, theobromine and theophylline.Leukotriene antagonists include, but are not limited to, montelukast,tomelukast, pranlukast and zafirlukast. 5-LO inhibitors include, but arenot limited to, zileuton, VIA-2291 (ABT761), AZ-4407 and ZD-2138 andcompounds found in US 2007/0149579, WO2007/016784.

In another specific embodiment described herein, methods for treatingPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of rhinitis, comprises administration to a patient compounds,pharmaceutical compositions, or medicaments described herein incombination with at least one additional agent selected from, by way ofexample only, antihistamines, leukotriene antagonists, corticosteroidsand decongestants. Leukotriene antagonists include, but are not limitedto, montelukast, tomelukast, pranlukast and zafirlukast.

In another aspect, methods for treating PGD₂-dependent or PGD₂ mediatedconditions or diseases, include administering a DP₂ antagonist describedherein in combination with other agents to treat respiratory diseases orconditions. Therapeutic agents used in the treatment of respiratoryconditions and disorders, such as, but not limited to asthma, include:glucocorticoids, such as, ciclesonide, beclomethasone, budesonide,flunisolide, fluticasone, mometasone, and triamcinolone; leukotrienemodifiers, such as, montelukast, zafirlukast, pranlukast, and zileuton;mast cell stabilizers, such as, cromoglicate (cromolyn), and nedocromil;antimuscarinics/anticholinergics, such as, ipratropium, oxitropium, andtiotropium; methylxanthines, such as, theophylline and aminophylline;antihistamine, such as, mepyramine (pyrilamine), antazoline,diphenhydramine, carbinoxamine, doxylamine, clemastine, dimenhydrinate,pheniramine, chlorphenamine (chlorpheniramine), dexchlorphenamine,brompheniramine, triprolidine, cyclizine, chlorcyclizine, hydroxyzine,meclizine, promethazine, alimemazine (trimeprazine), cyproheptadine,azatadine, ketotifen, acrivastine, astemizole, cetirizine, loratadine,mizolastine, terfenadine, fexofenadine, levocetirizine, desloratadine,fexofenadine; omalizumab, an IgE blocker; beta2-adrenergic receptoragonists, such as: short acting beta2-adrenergic receptor agonists, suchas, salbutamol (albuterol), levalbuterol, terbutaline, pirbuterol,procaterol, metaproterenol, fenoterol, bitolterol mesylate; andlong-acting beta2-adrenergic receptor agonists, such as, salmeterol,formoterol, bambuterol.

In one aspect, DP₂ antagonists described herein are administered incombination with one or more agents used to treat used to treat asthma,including, but not limited to: combination inhalers (fluticasone andsalmeterol oral inhalation (e.g. Advair)); inhaled Beta-2 agonists(albuterol inhaler; albuterol nebulizer solution; formoterol;isoproterenol oral inhalation; levalbuterol; metaproterenol inhalation;pirbuterol acetate oral inhalation; salmeterol aerosol inhalation;salmeterol powder inhalation; terbutaline inhaler); inhaledcorticosteroids (beclomethasone oral inhalation; budesonide inhalationsolution; budesonide inhaler; flunisolide oral inhalation; fluticasoneinhalation aerosol; fluticasone powder for oral inhalation; mometasoneinhalation powder; triamcinolone oral inhalation); leukotriene modifiers(montelukast; zafirlukast; zileuton); mast cell stabilizers (cromolyninhaler; nedocromil oral inhalation); monoclonal antibodies(omalizumab); oral Beta-2 agonists (albuterol oral syrup; albuterol oraltablets; metaproterenol; terbutaline); bronchodilator (aminophylline;oxtriphylline; theophylline).

In one aspect, DP₂ antagonists described herein are administered incombination with one or more agents used to treat allergy, including,but not limited to: antihistamine and decongestant combinations(cetirizine and pseudoephedrine; desloratadine and pseudoephedrine ER;fexofenadine and pseudoephedrine; loratadine and pseudoephedrine);antihistamines (azelastine nasal spray; brompheniramine; brompheniramineoral suspension; carbinoxamine; cetirizine; chlorpheniramine;clemastine; desloratadine; dexchlorpheniramine ER; dexchlorpheniramineoral syrup; diphenhydramine oral; fexofenadine; loratadine;promethazine); decongestants (pseudoephedrine); leukotriene modifiers(montelukast; montelukast granules); nasal anticholinergics(ipratropium); nasal corticosteroids (beclomethasone nasal inhalation;budesonide nasal inhaler; flunisolide nasal inhalation; fluticasonenasal inhalation; mometasone nasal spray; triamcinolone nasalinhalation; triamcinolone nasal spray); nasal decongestants(phenylephrine); nasal mast cell stabilizers (cromolyn nasal spray).

In one aspect, DP₂ antagonists described herein are administered incombination with one or more agents used to treat chronic obstructivepulmonary disease (COPD), including, but not limited to:anticholinergics-ipratropium bromide oral inhalation); combinationInhalers (albuterol and ipratropium (e.g. Combivent, DuoNeb);fluticasone and salmeterol oral inhalation (e.g. Advair));corticosteroids (dexamethasone tablets; fludrocortisone acetate;hydrocortisone tablets; methylprednisolone; prednisolone liquid;prednisone oral; triamcinolone oral); inhaled Beta-2 Agonists (albuterolinhaler; albuterol nebulizer solution; formoterol; isoproterenol oralinhalation; levalbuterol; metaproterenol inhalation; pirbuterol acetateoral inhalation; salmeterol aerosol inhalation; salmeterol powderinhalation; terbutaline inhaler); inhaled Corticosteroids(beclomethasone oral inhalation; budesonide inhalation solution;budesonide inhaler; flunisolide oral inhalation; fluticasone inhalationaerosol; fluticasone powder for oral inhalation; triamcinolone oralinhalation); mukolytics (guaifenesin); oral Beta-2 agonists (albuteroloral syrup; albuterol oral tablets; metaproterenol; terbutaline);bronchodilator (aminophylline; oxtriphylline; theophylline).

In one embodiment, DP₂ antagonists described herein are administered toa patient in combination with inhaled corticosteroids.

In one embodiment, DP₂ antagonists described herein are administered toa patient in combination with beta2-adrenergic receptor agonists. In oneembodiment, DP₂ antagonists described herein are administered to apatient in combination with short acting beta2-adrenergic receptoragonists. In one embodiment, DP₂ antagonists described herein areadministered to a patient in combination with long-actingbeta2-adrenergic receptor agonists.

Use of DP₂ Antagonists to Diagnose a Patient with a PGD₂-Dependent orPGD₂ Mediated Disease or Condition

As discussed herein, the administration of compounds of any of Formula(I), Formula (II), Formula (III), Formula (IV), or Formula (V) isdesigned to antagonize the activity of DP₂. For example, in specificembodiments, the administration of a DP₂ inhibitor decreases signaltransduction initiated by PGD₂ within the individual.

Thus, in accordance with one aspect, methods described herein includethe diagnosis or determination of whether or not a patient is sufferingfrom a PGD₂-dependent or PGD₂ mediated disease or condition byadministering to the subject a compound of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) or pharmaceutical compositionor medicament which includes a compound of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) and determining whether ornot the patient responds to the treatment.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits cancomprise a carrier, package, or container that is compartmentalized toreceive one or more containers such as vials, tubes, and the like, eachof the container(s) comprising one of the separate elements to be usedin a method described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers are formed fromany acceptable material including, e.g., glass or plastic.

For example, the container(s) can comprise one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically comprise one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for use of a compound described herein. Non-limiting examplesof such materials include, but not limited to, buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use. A set of instructions will alsotypically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein.

Example 1 Synthesis of{3-[3-(Benzyloxycarbonylamino-methyl)-pyridin-2-yl]-4-methoxy-phenyl}-aceticacid (Compound 1-1)

Step 1: (3-Bromo-4-methoxy-phenyl)-acetic acid ethyl ester

To 3-bromo-4-methoxyphenylacetic acid (24 g, 97 9 mmol) in EtOH (240 mL)was added thionyl chloride (7.8 mL, 107.7 mmol), and the reaction wasstirred for 35 minutes. Once no starting material was seen by analyticalLCMS, the mixture was quenched with NaHCO₃ until the solution was basic,and then extracted twice with CH₂Cl₂. The combined organic layers weredried over MgSO₄, filtered, and concentrated to give the title compound.

Step 2:[4-Methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-aceticacid ethyl ester

(3-Bromo-4-methoxy-phenyl)-acetic acid ethyl ester (27.4 g, 100.3 mmol),bis(pinacolato)diboron (25.47 g, 100.3 mmol), and potassium acetate(24.6 g, 98.250.8 mmol) were combined in 1,4-dioxane (250 mL), and thesolution was purged with N₂ for 20 minutes.(1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (4.10 g,5.02 mmol) was added, and the reaction was stirred at 110° C. overnight.The mixture was cooled to room temperature and filtered through Celite,and the filtrate was diluted with EtOAc and brine. The aqueous layer wasseparated and extracted twice with EtOAc, and the combined organiclayers were dried and concentrated. The crude material was purified bysilica gel chromatography (20-60% EtOAc in hexanes) to give the titlecompound.

Step 3: [3-(3-Cyano-pyridin-2-yl)-4-methoxy-phenyl]-acetic acid ethylester

[4-Methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-aceticacid ethyl ester (0.672 g, 2.1 mmol), 2-chloro-3-pyridinecarbonitrile(0.274 g, 2 0 mmol), and potassium carbonate (0.966 g, 7.0 mmol) werecombined in deoxygenated 2:1 DME:H₂O (21 mL).Tetrakis(triphenylphosphine)palladium(0) (0.115, 0.1 mmol) was added,and the reaction was stirred at 70° C. for 1 hour. Once no startingmaterial was seen by analytical LCMS and tic, the mixture was worked-upand purified by silica gel chromatography to give the title compound.

Step 4: [3-(3-Aminomethyl-pyridin-2-yl)-4-methoxy-phenyl]acetic acidmethyl ester

[3-(3-Cyano-pyridin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester(0.579 g, 2.0 mmol) was dissolved in MeOH (20 mL) and 12N aqueous HCl (4mL). After the mixture was purged with N₂, 10% palladium on carbon (50wt % w/w; 0.300 g, 0.15 mmol) was added, and the reaction was stirredovernight under 55 psi of H₂ using a Parr shaker. After stirring for 18hours, the mixture was filtered and neutralized with 1N aqueous NaOH (50mL), and then concentrated to remove MeOH. The residue was partitionedbetween EtOAc and H2O, and the organic layer was separated and washedfive times with water. The organic layer was dried, filtered, andconcentrated to give the title compound.

Step 5:{3-[3-(Benzyloxycarbonylamino-methyl)-pyridin-2-yl]-4-methoxy-phenyl}-aceticacid methyl ester

[3-(3-Aminomethyl-pyridin-2-yl)-4-methoxy-phenyl]-acetic acid methylester (0.140 g, 0.49 mmol) and triethylamine (0.17 mL, 1.23 mmol) wasdissolved in CH₂Cl₂ (5 mL). Benzyl chloroformate (0.08 mL, 0.54 mmol)was added, and the reaction was stirred for 1 hour. Once no startingmaterial was seen by analytical LCMS, the mixture was purified bypreparative HPLC to give the title compound.

Step 6:{3-[3-(Benzyloxycarbonylamino-methyl)-pyridin-2-yl]-4-methoxy-phenyl}-aceticacid

{3-[3-(Benzyloxycarbonylamino-methyl)-pyridin-2-yl]-4-methoxy-phenyl}-aceticacid methyl ester was hydrolyzed to give the title compound.

Example 2 Synthesis of(3-{3-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-5-methyl-pyridin-2-yl}-4-methoxy-phenyl)-aceticacid (Compound 1-2)

Step 1: Benzyl-prop-(E)-ylidene-amine

To an ice-cold solution of benzylamine (20.0 g, 184 mmol) was addedpropionaldehyde (10.8 g, 184 mmol) over 1 hour. Potassium hydroxide (5.2g, 92.7 mmol) was added, and the reaction was allowed to stand for 1hour, during which time the solution separated into two layers. Theorganic layer was isolated and stored over potassium hydroxide pelletsovernight in the refrigerator to give the product as a cloudy liquid,which was used without further purification.

Step 2: N-Benzyl-N-((E)-propenyl)-acetamide

To benzyl-prop-(E)-ylidene-amine (6.0 g, 40 mmol) in triethylamine (5.67mL, 40 mmol) at 0° C. was slowly added acetic anhydride (3.81 mL, 40mmol), and the reaction was stirred for 30 minutes at 0° C. and thenovernight at room temperature. The mixture was concentrated, and theresidue was purified by silica gel chromatography (0-25% EtOAc inhexanes) to give the title compound.

Step 3: 2-Chloro-5-methyl-pyridine-3-carbaldehyde

DMF (2.86 mL, 37 0 mmol) was added slowly over 2 minutes to an ice-coldsolution of N-benzyl-N-((E)-propenyl)-acetamide (1.0 g, 5.3 mmol) andphosgene (20% in toluene; 18.3 mL, 37.0 mmol). After stirring for 30minutes at 0° C., the ice bath was removed, and the reaction was stirredat room temperature for 2 hours, and then heated to 75° C. for 4.5hours. The mixture was poured over ice and extracted with CH₂Cl₂. Theorganic layer was dried over MgSO₄, filtered, and concentrated, and theresidue was purified by silica gel chromatography (0-50% EtOAc inhexanes) to give the title compound.

Step 4: (2-Chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-amine

2-Chloro-5-methyl-pyridine-3-carbaldehyde (0.22 g, 1.41 mmol),ethylamine (2M in THF; 1.06 mL, 2.12 mmol), and sodium cyanoborohydride(0.133 g, 2.12 mmol) were combined in MeOH (2.52 mL). Acetic acid (0.12mL, 2.12 mmol) was added, and the reaction was stirred at roomtemperature for 1 hour. The mixture was concentrated, and the residuewas dissolved in CH₂Cl₂, washed with saturated aqueous NaHCO₃,concentrated, and purified by silica gel chromatography (0-10% MeOH inCH₂Cl₂) to give the title compound.

Step 5: Cyclopropanecarboxylic acid(2-chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-amide

(2-Chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-amine (0.126 g, 0.69 mmol),cyclopropanecarboxylic acid (0.08 mL, 1.03 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.197 g,1.03 mmol), 1-hydroxybenzotriazole hydrate (0.139 g, 1.03 mmol), andtriethylamine (0.29 mL, 2.05 mmol) were combined in CH₂Cl₂ and stirredat room temperature over the weekend. The mixture was concentrated andpurified by silica gel chromatography (0-70% EtOAc in hexanes) to givethe title compound.

Step 6:(3-{3-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-5-methyl-pyridin-2-yl}-4-methoxy-phenyl)-aceticacid ethyl ester

Cyclopropanecarboxylic acid(2-chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-amide (0.120 g, 0.48 mmol),[4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-aceticacid ethyl ester (0.183 g, 0.57 mmol), and potassium carbonate (0.198 g,1.43 mmol) were combined in DME and H₂O. The mixture was purged with N₂for 10 minutes, and then tetrakis(triphenylphosphine)palladium(0) (0.055g, 0.05 mmol) was added, and the reaction was stirred at 80° C. for 2hours. Once no starting material was seen by analytical tlc, the mixturewas diluted with H₂O and extracted three times with EtOAc. The combinedorganic layers were washed with H₂O and brine, dried over Na₂SO₄,decanted, and concentrated, and the residue was purified by silica gelchromatography (0-70% EtOAc in hexanes) to give the title compound.

Step 7:(3-{3-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-5-methyl-pyridin-2-yl}-4-methoxy-phenyl)-aceticacid

To(3-{3-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-5-methyl-pyridin-2-yl}-4-methoxy-phenyl)-aceticacid ethyl ester (0.154 g, 0.38 mmol) in THF (1.5 mL) was added 1Naqueous LiOH (1.14 mL, 1.14 mmol), and enough MeOH to clarify thesolution. The reaction was stirred at 40° C. for 30 minutes, until nostarting material was seen by analytical tlc. The mixture wasconcentrated, diluted with H₂O, and washed twice with EtOAc. Afterfiltering through a 25 μM nylon filter, the aqueous layer was acidifiedto pH 3 with 1N aqueous HCl, and the volume was reduced by half and thensaturated with NH₄Cl. The mixture was extracted five times with CH₂Cl₂,and then the aqueous layer was concentrated to leave residual salts anda trace of liquid, which was further extracted with CH₂Cl₂ until only asmall amount of the desired product remained in the salts. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated togive the title compound.

Example 3 Synthesis of[3-(3-{[Ethyl-(3-phenyl-propionyl)-amino]-methyl}-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-aceticacid (Compound 1-3)

Step 1: (2-Chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-carbamic acidtert-butyl ester

To (2-chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-amine (0.59 g, 3.21mmol) in CH₂Cl₂ (10 mL) was added di-tert-butyl dicarbonate (1.05 g,4.81 mmol), and the reaction was stirred at room temperature for 30minutes. The mixture was washed with saturated aqueous NaHCO₃, H₂O, andbrine, and then dried over Na₂SO₄, decanted, and concentrated. Theresidue was purified by silica gel chromatography (0-50% EtOAc inhexanes) to give the title compound.

Step 2:(3-{3-[(tert-Butoxycarbonyl-ethyl-amino)-methyl]-5-methyl-pyridin-2-yl}-4-methoxy-phenyl)-aceticacid ethyl ester

Prepared according to the procedure described in Example 2, Step 6,using the following starting materials:(2-chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-carbamic acid tert-butylester and[4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-aceticacid ethyl ester.

Step 3:[3-(3-Ethylaminomethyl-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-aceticacid ethyl ester, trifluoroacetate

(3-{3-[(tert-Butoxycarbonyl-ethyl-amino)-methyl]-5-methyl-pyridin-2-yl}-4-methoxy-phenyl)-aceticacid ethyl ester (1.09 mmol) was treated with trifluoroacetic acid (2.5mL) in CH₂Cl₂ (5 mL) for 2 hours at room temperature, until no startingmaterial was seen by analytical tlc. The mixture was concentratedseveral times from CH₂Cl₂ to give the title compound.

Step 4:[3-(3-{[Ethyl-(3-phenyl-propionyl)-amino]-methyl}-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-aceticacid ethyl ester

[3-(3-Ethylaminomethyl-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-aceticacid ethyl ester, trifluoroacetate (0.36 mmol) was reacted withhydrocinnamoyl chloride (0.06 mL, 0.44 mmol) and triethylamine (0.15 mL,1.09 mmol) in CH₂Cl₂ to give the title compound.

Step 5:[3-(3-{[Ethyl-(3-phenyl-propionyl)-amino]-methyl}-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-aceticacid

[3-(3-{[Ethyl-(3-phenyl-propionyl)-amino]-methyl}-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-aceticacid ethyl ester was hydrolyzed with 1N aqueous LiOH to give the titlecompound.

Example 4 Synthesis of{3-[3-(3-Benzyl-1-ethyl-ureidomethyl)-5-methyl-pyridin-2-yl]-4-methoxy-phenyl}-aceticacid (Compound 1-4)

Step 1:{3-[3-(3-Benzyl-1-ethyl-ureidomethyl)-5-methyl-pyridin-2-yl]-4-methoxy-phenyl}-aceticacid ethyl ester

[3-(3-Ethylaminomethyl-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-aceticacid ethyl ester, trifluoroacetate (0.36 mmol) was reacted with benzylisocyanate (0.05 mL, 0.44 mmol) and triethylamine (0.152 mL, 1.09 mmol)in CH₂Cl₂ to give the title compound.

Step 2:{3-[3-(3-Benzyl-1-ethyl-ureidomethyl)-5-methyl-pyridin-2-yl]-4-methoxy-phenyl}-aceticacid

{3-[3-(3-Benzyl-1-ethyl-ureidomethyl)-5-methyl-pyridin-2-yl]-4-methoxy-phenyl}-aceticacid ethyl ester was hydrolyzed with 1N aqueous LiOH to give the titlecompound.

Example 5 Synthesis of(3-{3-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-aceticacid (Compound 2-1)

Step 1: (2-Chloro-quinolin-3-ylmethyl)-ethyl-amine

2-Chloro-3-quinolinecarboxaldehyde (2.0 g, 10 4 mmol), ethylamine (2M inMeOH, 5.2 mL, 10.4 mmol), and acetic acid (0.65 mL, 11.4 mmol) werecombined in MeOH (15 mL) and stirred at room temperature for 30 minutesuntil all materials were completely dissolved. Sodium cyanoborohydride(1.31 g, 20.9 mmol) was added portionwise over 5 minutes, and thereaction was stirred for 1 hour. The mixture was worked-up withsaturated aqueous NaHCO₃ and extracted with CH₂Cl₂, and the residue waspurified by silica gel chromatography (0-5% MeOH in CH₂Cl₂) to give thetitle compound.

Step 2: (2-Chloro-quinolin-3-ylmethyl)-ethyl-carbamic acid tert-butylester

To (2-chloro-quinolin-3-ylmethyl)-ethyl-amine (1.35 g, 6.1 mmol) inCH₂Cl₂ (20 mL) was added di-tert-butyl dicarbonate (0.153 g, 0.70 mmol),and the reaction was stirred until no starting material remained. Themixture was partitioned between CH₂Cl₂ and saturated aqueous NaHCO₃, andthe organic layer was separated, dried over MgSO₄, filtered, andconcentrated to give the title compound.

Step 3:(3-{3-[(tert-Butoxycarbonyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-aceticacid ethyl ester

(2-Chloro-quinolin-3-ylmethyl)-ethyl-carbamic acid tert-butyl ester (1.0g, 3.11 mmol),[4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-aceticacid ethyl ester (1.07 g, 3.34 mmol), potassium carbonate (1.08 g, 7.8mmol), and catalytic tetrakis(triphenylphosphine)palladium(0) werecombined in 2:1 DME:H₂O (18 mL), and stirred at 80° C. for 6 hours.After standard work-up, the residue was purified by silica gelchromatography to give the title compound.

Step 4: [3-(3-Ethylaminomethyl-quinolin-2-yl)-4-methoxy-phenyl]-aceticacid ethyl ester, dihydrochloride

(3-{3-[(tert-Butoxycarbonyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-aceticacid ethyl ester (1.18 g, 2.46 mmol) in CH₂Cl₂ (10 mL) was treated withhydrogen chloride (4N in 1,4-dioxane; 5 mL, 20.0 mmol) at roomtemperature for 3 hours. The mixture was concentrated to give the titlecompound.

Step 5:(3-{3-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-aceticacid ethyl ester

[3-(3-Ethylaminomethyl-quinolin-2-yl)-4-methoxy-phenyl]-acetic acidethyl ester, dihydrochloride (0.40 g, 0.89 mmol) anddiisopropylethylamine (1.0 mL, 5.74 mmol) were combined in CH₂Cl₂ (5 mL)and stirred for 5 minutes. Cyclopropanecarbonyl chloride (0.09 mL, 0.99mmol) was added, and the reaction was stirred at room temperature untilno starting material was seen by analytical LCMS. The mixture waspartitioned between CH₂Cl₂ and saturated aqueous NaHCO₃, and the aqueouslayer was extracted with CH₂Cl₂. The combined organic layers were driedover MgSO₄, filtered, and concentrated, and the residue was purified bysilica gel chromatography (0-75% EtOAc in hexanes) to give the titlecompound.

Step 6:(3-{3-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-aceticacid

(3-{3-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-aceticacid ethyl ester (0.272 g, 0.61 mmol) in THF (5 mL) and H₂O (2 mL) wastreated with lithium hydroxide (0.090 g, 2.1 mmol) and stirred at roomtemperature until no starting material was seen by analytical LCMS. Themixture was diluted with EtOAc and H₂O, and citric acid was added toacidify the solution. The mixture was extracted with EtOAc, and thecombined organic layers were washed with H₂O, dried over MgSO₄, filteredand concentrated to give the title compound.

Example 6 Synthesis of(3-{3-[(Acetyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-aceticacid (Compound 2-2)

Step 1:(3-{3-[(Acetyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-aceticacid ethyl ester

Prepared according to the procedure described in Example 5, Step 5,using the following starting materials:[3-(3-ethylaminomethyl-quinolin-2-yl)-4-methoxy-phenyl]-acetic acidethyl ester; dihydrochloride and acetic anhydride.

Step 2:(3-{3-[(Acetyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-aceticacid

Prepared according to the procedure described in Example 5, Step 6,using the following starting material:(3-{3-[(acetyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-aceticacid ethyl ester.

Example 7 Synthesis of[3-(3-{[Ethyl-(2-methoxy-acetyl)-amino]-methyl}-quinolin-2-yl)-4-methoxy-phenyl]-aceticacid (Compound 2-3)

Step 1:[3-(3-{[Ethyl-(2-methoxy-acetyl)-amino]-methyl}-quinolin-2-yl)-4-methoxy-phenyl]-aceticacid ethyl ester

Prepared according to the procedure described in Example 5, Step 5,using the following starting materials:[3-(3-ethylaminomethyl-quinolin-2-yl)-4-methoxy-phenyl]-acetic acidethyl ester; dihydrochloride and methoxyacetyl chloride.

Step 2:[3-(3-{[Ethyl-(2-methoxy-acetyl)-amino]-methyl}-quinolin-2-yl)-4-methoxy-phenyl]-aceticacid

Prepared according to the procedure described in Example 5, Step 6,using the following starting material:[3-(3-{[ethyl-(2-methoxy-acetyl)-amino]-methyl}-quinolin-2-yl)-4-methoxy-phenyl]-aceticacid ethyl ester.

Example 8 Synthesis of(3-{2-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid (Compound 2-4)

Step 1: 3-Bromo-quinoline-2-carbaldehyde

To isopropylmagnesium chloride lithium chloride complex solution (1.3Min THF; 50 mL, 65 mmol) was added 2,2,6,6-tetramethylpiperidine (11.5mL, 68.3 mmol) dropwise, and the mixture was stirred overnight at roomtemperature. To 55 mL of the resulting solution at −25° C. under N₂ wasadded 3-bromoquinoline (6.52 mL, 48 mmol) dropwise, and the reaction wasstirred for 1 hour. DMF (3 mL) was added, and the reaction was slowlywarmed to room temperature and monitored by analytical LCMS. The mixturewas quenched with saturated aqueous NH₄Cl and worked-up. The residue waspurified by silica gel chromatography to give the title compound.

Step 2: (3-Bromo-quinolin-2-ylmethyl)-ethyl-amine

3-Bromo-quinoline-2-carbaldehyde (3.34 g, 16 3 mmol), ethylamine (2M inMeOH; 9.78 mL, 19.6 mmol), and acetic acid (1.02 mL, 17.8 mmol) werecombined in MeOH (25 mL) and stirred at 0° C. for 30 minutes. Sodiumcyanoborohydride (1.53 g, 24.5 mmol) was added, and the reaction wasmonitored by analytical LCMS. The mixture was worked-up with saturatedaqueous NaHCO₃ and extracted with CH₂Cl₂, and the residue was purifiedby silica gel chromatography (0-5% MeOH in CH₂Cl₂) to give the titlecompound.

Step 3: (3-Bromo-quinolin-2-ylmethyl)-ethyl-carbamic acid tert-butylester

Prepared according to the procedure described in Example 5, Step 2,using the following starting materials:(3-bromo-quinolin-2-ylmethyl)-ethyl-amine and di-tert-butyl dicarbonate.

Step 4:(3-{2-[(tert-Butoxycarbonyl-ethyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid ethyl ester

Prepared according to the procedure described in Example 5, Step 3,using the following starting materials:(3-bromo-quinolin-2-ylmethyl)-ethyl-carbamic acid tert-butyl ester and[4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-aceticacid ethyl ester.

Step 5: [3-(2-Ethylaminomethyl-quinolin-3-yl)-4-methoxy-phenyl]-aceticacid ethyl ester, dihydrochloride

Prepared according to the procedure described in Example 5, Step 4,using the following starting material:(3-{2-[(tert-butoxycarbonyl-ethyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid ethyl ester.

Step 6:(3-{2-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid ethyl ester

Prepared according to the procedure described in Example 5, Step 5,using the following starting materials:[3-(2-ethylaminomethyl-quinolin-3-yl)-4-methoxy-phenyl]-acetic acidethyl ester, dihydrochloride and cyclopropanecarbonyl chloride.

Step 7:(3-{2-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid

Prepared according to the procedure described in Example 5, Step 6,using the following starting material:(3-{2-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid ethyl ester.

Example 9 Synthesis of(3-{2-[(Ethyl-propionyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid (Compound 2-5)

Step 1:(3-{2-[(Ethyl-propionyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid ethyl ester

Prepared according to the procedure described in Example 5, Step 5,using the following starting materials:[3-(2-ethylaminomethyl-quinolin-3-yl)-4-methoxy-phenyl]-acetic acidethyl ester, dihydrochloride and propionyl chloride.

Step 2:(3-{2-[(Ethyl-propionyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid

Prepared according to the procedure described in Example 5, Step 6,using the following starting material:(3-{2-[(ethyl-propionyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid ethyl ester.

Example 10 Synthesis of[3-(2-{[Ethyl-(2-methoxy-acetyl)-amino]-methyl}-quinolin-3-yl)-4-methoxy-phenyl]-aceticacid (Compound 2-6)

Step 1:[3-(2-{[Ethyl-(2-methoxy-acetyl)-amino]-methyl}-quinolin-3-yl)-4-methoxy-phenyl]-aceticacid ethyl ester

Prepared according to the procedure described in Example 5, Step 5,using the following starting materials:[3-(2-ethylaminomethyl-quinolin-3-yl)-4-methoxy-phenyl]-acetic acidethyl ester, dihydrochloride and methoxyacetyl chloride.

Step 2:[3-(2-{[Ethyl-(2-methoxy-acetyl)-amino]-methyl}-quinolin-3-yl)-4-methoxy-phenyl]-aceticacid

Prepared according to the procedure described in Example 5, Step 6,using the following starting material:[3-(2-{[ethyl-(2-methoxy-acetyl)-amino]-methyl}-quinolin-3-yl)-4-methoxy-phenyl]-aceticacid ethyl ester.

Example 11 Synthesis of(3-{2-[(Acetyl-benzyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid (Compound 2-7)

Step 1: Benzyl-(3-bromo-quinolin-2-ylmethyl)-amine

Prepared according to the procedure described in Example 8, Step 2,using the following starting materials: 3-bromo-quinoline-2-carbaldehydeand benzylamine

Step 2: Benzyl-(3-bromo-quinolin-2-ylmethyl)-carbamic acid tert-butylester

Prepared according to the procedure described in Example 5, Step 2,using the following starting materials:benzyl-(3-bromo-quinolin-2-ylmethyl)-amine and di-tert-butyldicarbonate.

Step 3:(3-{2-[(Benzyl-tert-butoxycarbonyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid ethyl ester

Prepared according to the procedure described in Example 5, Step 3,using the following starting materials:benzyl-(3-bromo-quinolin-2-ylmethyl)-carbamic acid tert-butyl ester and[4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-aceticacid ethyl ester.

Step 4:{3-[2-(Benzylamino-methyl)-quinolin-3-yl]-4-methoxy-phenyl}-acetic acidethyl ester, dihydrochloride

Prepared according to the procedure described in Example 5, Step 4,using the following starting material:(3-{2-[(benzyl-tert-butoxycarbonyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid ethyl ester.

Step 5:(3-{2-[(Acetyl-benzyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid ethyl ester

Prepared according to the procedure described in Example 5, Step 5,using the following starting materials:{3-[2-(benzylamino-methyl)-quinolin-3-yl]-4-methoxy-phenyl}-acetic acidethyl ester, dihydrochloride and acetic anhydride.

Step 6:(3-{2-[(Acetyl-benzyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid

Prepared according to the procedure described in Example 5, Step 6,using the following starting material:(3-{2-[(acetyl-benzyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid ethyl ester.

Example 12 Synthesis of(3-{2-[(Benzyl-cyclopropanecarbonyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid (Compound 2-8)

Step 1:(3-{2-[(Benzyl-cyclopropanecarbonyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid ethyl ester

Prepared according to the procedure described in Example 5, Step 5,using the following starting materials:{3-[2-(benzylamino-methyl)-quinolin-3-yl]-4-methoxy-phenyl}-acetic acidethyl ester, dihydrochloride and cyclopropanecarbonyl chloride.

Step 2:(3-{2-[(Benzyl-cyclopropanecarbonyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid

Prepared according to the procedure described in Example 5, Step 6,using the following starting material:(3-{2-[(benzyl-cyclopropanecarbonyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid ethyl ester.

Mass spectrometric data for compounds described in the Examples aredisplayed in Table 1 and Table 2.

Example 13 CRTH2 Assays Example 13a DP₂/CRTH2 Binding Assay

The ability of a compound to bind to the human DP₂ receptor is assessedvia a radioligand binding assay using [³H]PGD₂. HEK293 cells stablyexpressing recombinant human DP₂ are resuspended in 10 mM Hepes, 7.4containing 1 mM DTT, lysed and centrifuged at 75,000×g to pellet themembranes. The membranes are resuspended in 10 mM Hepes, 7.4 containing1 mM DTT and 10% glycerol to approximately 5 mg protein/ml. Membranes(2-10 μg protein/well) are incubated in 96-well plates with 1 nM[³H]PGD₂ and test compound in Assay Buffer (50 mM Hepes, 10 mM MnCl₂, 1mM EDTA, plus or minus 0.2% human serum albumin, pH 7.4) for 60 minutesat room temperature. The reactions are terminated by rapid filtrationthrough Whatman GF/C glass fibre filter plates. The filter plates werepre-soaked in 0.33% polyethylenimine for 30 minutes at room temperaturethen washed in Wash Buffer (50 mM Hepes, 0.5 M NaCl pH 7.4) prior toharvesting. After harvesting, the filter plates are washed 3 times with1 ml cold Wash Buffer then dried. Scintillant is then added to theplates and the radioactivity retained on the filters is determined on aPackard TopCount (Perkin Elmer). Specific binding is determined as totalradioactive binding minus non-specific binding in the presence of 10 μMPGD₂. IC₅₀s were determined using GraphPad prism analysis of drugtitration curves. Compounds tested had an IC₅₀ of less than 100micromolar in this assay.

Example 13b GTPγS Binding Assay

The ability of a compound to inhibit binding of GTP to DP₂ is assessedvia a membrane GTPγS assay. CHO cells stably expressing the recombinanthuman CRTH2 receptor are resuspended in 10 mM Hepes, 7.4 containing 1 mMDTT, lysed and centrifuged at 75,000×g to pellet the membranes. Themembranes are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT and10% glycerol. Membranes (˜12.5 μg per well) are incubated in 96-wellplates with 0.05 nM [³⁵S]-GTPγS, 80 nM PGD₂, 5 μM GDP, and test compoundin Assay Buffer (50 mM Hepes, pH 7.4, 100 mM NaCl, 5 mM MgCl₂ and 0.2%human serum albumin) for 60 minutes at 30° C. The reactions areterminated by rapid filtration through Whatman GF/B glass fibre filterplates. The filter plates are washed 3 times with 1 ml cold Assay Bufferand dried. Scintillant is then added to the plates and the radioactivityretained on the filters is determined on a Packard TopCount (PerkinElmer). Specific binding is determined as total radioactive bindingminus non-specific binding in the absence of the ligand (80 nM PGD₂).IC₅₀s were determined using Graphpad prism analysis of drug titrationcurves.

Example 13c Whole Blood Esoinophil Shape Change Assay

Blood is drawn from consenting human volunteers in EDTA vacutainer tubesand used within 1 hr of draw. A 98 μl aliquot of blood is mixed with 2μl of test compound (in 50% DMSO) in 1.2 ml polypropylene tubes. Theblood is vortexed and incubated at 37° C. for 15 minutes. 5 μl of 1 μMPGD₂ in PBS is added for a final concentration of 50 nM and the tubesbriefly vortexed. The reactions are incubated for exactly 5 minutes at37° C. and then terminated by placing the tubes on ice and immediatelyadding 250 μl of ice-cold 1:4 diluted Cytofix (BD Biosciences). Thereactions are transferred to 12×75 mM polystyrene round bottom tubes andthe red blood cells lysed by the addition of 3 ml ammonium chloridelysing solution (150 mM NH₄Cl, 10 mM KHCO₃, 0.1 mM EDTA disodium salt)and incubation at room temperature for 15 minutes. The cells arepelleted by spinning at 1300 rpm for 5 minutes at 4° C. and washed oncewith 3 ml ice-cold PBS. The cells are resuspended in 0.2 ml of ice-cold1:4 diluted Cytofix (BD Biosciences) and analyzed on a FACSCalibur (BDBiosciences) within 2 hours. Eosinophils were gated on the basis ofautofluorescence in the FL2 channel and shape change on 500 eosinophilswas assayed by forward scatter and side scatter analysis. The specificchange in shape induced by PGD₂ was calculated as the difference betweenthe percentage of high forward scatter eosinophils in the presence andabsence of PGD₂. IC₅₀s were determined using Graphpad Prism® analysis ofdrug titration curves.

Example 13d DP₁ Binding Assay

The ability of a compound to bind to the human DP1 receptor wasevaluated via a radioligand membrane binding assay using the DP₁selective synthetic ligand [³H]BW A868C. Packed human platelets(Biological Specialty Corporation), were resuspended in 6 volumes ofHepes/HBSS buffer (10 mM Hepes, 1 mM DTT in Hanks Balanced Salt Solution(HBSS)), lysed and centrifuged at 75,000×g to pellet the membranes.Membranes were resuspended in Hepes/HBSS buffer to approximately 12 mgprotein/ml. Membranes (20 μg protein/well) are incubated in 96-wellplates with 2 nM [³H]BWA868C and test compound in Assay Buffer (50 mMHepes, 10 mM MnCl₂, 1 mM EDTA, plus or minus 0.2% human serum albumin,pH 7.4) for 60 minutes at room temperature. The reactions are terminatedby rapid filtration through Whatman GF/C glass fibre filter plates. Thefilter plates were pre-soaked in 0.33% polethylenimine for 30 minutes atroom temperature then washed in Wash Buffer (50 mM Hepes, 0.5 M NaCl pH7.4) prior to harvesting. After harvesting, the filter plates are washed3 times with 1 ml cold Wash Buffer then dried. Scintillant is then addedto the plates and the radioactivity retained on the filters isdetermined on a Packard TopCount (Perkin Elmer). Specific binding isdetermined as total radioactive binding minus non-specific binding inthe presence of 10 μM BW A868C. IC₅₀s were determined using GraphPadprism analysis of drug titration curves.

Example 14 In Vivo Assay Mouse Allergic Rhinitis Model

The compounds ability to inhibit allergen-induced sneezing and nasalrubbing is assessed using a mouse model of allergic rhinitis. Methodswere adapted from those detailed in Nakaya, M., et al. 2006. Noninvasivesystem for evaluating allergen-induced nasal hypersensitivity in murineallergic rhinitis. Laboratory Investigation, 86:917-926. Female BALB/cmice (20-25 g) are immunized by an intraperitoneal injection (i.p.) of 2μg ovalbumin (OVA) complexed with alum in a volume 0.2 ml on days 0 and14. Seven days later (day 21) mice are challenged intranasally with 20μl of a 10 mg/ml solution of OVA.

The challenge period occurs daily from days 21 to day 25. Mice (5/group)are randomly assigned to receive either compound or vehicle and aretreated by oral gavage 1-2 hour prior to each OVA challenge. The numberof sneezes and nasal rubs are counted by an independent blind observeduring a period of 8 minutes immediately following OVA challenge on days21, 23 and 25. A significant increase in allergen-induced sneezing andnasal rubbing occurs over the 5-day challenge period. Inhibition of thiseffect by select compounds is determined statistically using Graphpadprism.

Example 15 Guinea Pig IV-DKPGD2-Induced Peripheral Blood LeukocyteInflux

The compounds ability to inhibit leukocyte migration in vivo wasassessed using intravenous injection of13,14-dihydro-15-keto-prostaglandin D2 (DK-PGD2). Methods were adaptedfrom those detailed Shichijo et al., 2003, Chemoattractantreceptor-homologous molecule expressed on Th2 cells activation in vivoincreases blood leukocyte counts and its blockade abrogates13,14-dihydro-15-keto-prostaglandin D2-induced eosinophilia in rats.Journal of Pharmacology and Experimental Therapeutics, 307:518-525. MaleHartley guinea pigs were immunized with ovalbumin (OVA) on day 0 byintraperitoneal (IP) injection of 1 ml of a 100 μg/ml solution in ImjectAlum. They were then used in the DK-PGD2 procedure between days 14 and21. Subjects were randomly assigned to receive either vehicle (0.5%methyl cellulose, 4 ml/kg, oral (PO)) or one of three to four doses oftest compound. Two hours or eighteen hours after dosing, animals wereanesthetized with ketamine and challenged with DK-PGD2 (1 mg/kg, IV).Thirty minutes after IV administration, blood was collected via themarginal ear vein into EDTA tubes for cell analysis. 10 μl blood waslysed in 190 μl water followed by a further 20-fold dilution in PBS. A10 μl fraction was mixed with equal parts trypan blue and loaded on ahemocytometer. Cells were visualized at a magnification of 40× using aLabPro light microscope and totals counted and recorded. Cells areexpressed as total cells×10⁸ per ml of blood. Inhibition of this effectby select compounds is determined statistically using Graphpad prism.

The compounds that were tested in Table 1 and Table 2 had IC₅₀ below 10μM in the hDP2 (CRTH2) binding assay.

TABLE 4 Representative Biological Data Compound Number hDP2 (μM)Compound 1-1 C Compound 1-2 B Compound 1-3 A Compound 1-4 A Compound 1-5A Compound 1-6 A Compound 1-7 B Compound 2-1 B Compound 2-2 C Compound2-3 C Compound 2-4 A Compound 2-5 A Compound 2-6 A Compound 2-7 ACompound 2-8 A Ramatroban B A = less than 0.3 μM; B = greater than 0.3μM and less than 1 μM; C = greater than 1 μM.

Example 16 Clinical Trials in Humans Study 1: Clinical Trial EvaluatingEffect of Compound of Formula (I), Formula (II), Formula (III), Formula(IV) or Formula (V) on Ex Vivo PGD2-Induced Blood Eosinophil ShapeChange

In this double-blind, randomized, placebo-controlled, single ascendingdose study of Compound of Formula (I), Formula (II), Formula (III),Formula (IV) or Formula (V) in healthy volunteers the inhibition of exvivo PGD2-induced blood eosinophil shape change is determined to showproof of biochemical mechanism of DP2 receptor antagonism. Eightsubjects (6 active, 2 placebo) per dose level are used. Pre dose bloodis drawn and challenged with PGD2 to determine baseline shape change asdescribed above in example 13. At varying times after dosing blood isdrawn for both pharmacokinetic analyses of drug concentration in blood,and also for PGD2 challenge and eosinophil shape change determination.The extent of receptor blockage is determined from the relationshipbetween drug blood concentration and percentage inhibition of eosinophilshape change.

Study 2: Clinical Trial Evaluating Effect of Compound of Formula (I),Formula (II), Formula (III), Formula (IV) or Formula (V) onAllergen-Induced Nasal Symptoms and Inflammatory and Allergic Biomarkers

In this double-blind, randomized, placebo-controlled study of Compoundof Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V)in individuals with allergic rhinitis the inhibition of nasal symptomsand allergic biomarkers is determined following nasal challenge withappropriate allergen. Fifteen subjects (10 active, 5 placebo) are used.Subjects are dosed for 7 days with either placebo or an amount ofcompound of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) that results in complete DP2 receptor block in an ex vivoPGD₂-induced blood eosinophil shape change pharmacodynamic study asdescribed above. On day 7 subjects undergo nasal allergen challenge (2hours post-dose) and early allergic response (0.25-1.0 hr) and lateallergic response (4-24 hr) are evaluated as an increase from baselinefor treated vs placebo. In addition changes in inflammatory celldifferentials, Th2 cytokines and other inflammatory markers aredetermined as increase from baseline for treated vs placebo.

Compound of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) Assay

The plasma concentrations of compound of Formula (I) are determined byLCMS-MS giving a detection limit in the range of 1-40 ng·ml-1.

Study 3: Vienna Challenge Chamber Study

Study design: The study is a randomised, double blind, placebocontrolled, two way crossover evaluation of compound of Formula (I),Formula (II), Formula (III), Formula (IV), or Formula (V), given orallyfor eight days. There is a screening period of one week and a washoutperiod of three weeks between the two treatment periods.

There is a follow up one week after the last dose of study drug. Thegroup of patients who receive the study drug for the first treatmentperiod and placebo for the second are designated group A, while thegroup of patients who receive placebo for the first treatment period andthe study drug for the second treatment period are designated group B.

Treatment plan and methods: The subjects undergo a complete screeningassessment to determine a baseline response to allergens. This screeningassessment takes place one week prior to the start of dosing.

Subjects commence dosing with compound of Formula (I), Formula (II),Formula (III), Formula (IV), or Formula (V), or placebo on Day 1 of eachtreatment period of the study. Adverse events, total nasal symptom scoreand concomitant medications are noted.

Subjects report back to the clinic on Day 2 of each treatment period fora 6 hour allergen challenge. The following measurements are obtained:

-   -   Total nasal symptom score (TNSS) (obstruction, rhinorrhoea,        itch, sneeze) with each symptom scored on a categorical scale        from 0 to 3 pre-challenge, every 15 mins from 0 to 6 h        post-start of challenge    -   Eye symptom score (watery eyes, itchy eyes, red eyes) with each        symptom scored on a categorical scale from 0 to 3 pre-challenge,        every 15 mins from 0 to 6 h post-start of challenge    -   Other symptoms (cough, itchy throat, itchy ears) with each        symptom scored on a categorical scale from 0 to 3 pre-challenge        and every 15 mins from 0 to 6 h post-start of challenge

Subjects report back to the clinic on Day 8 of each treatment period fora 6 hour allergen challenge and the measurements obtained on Day 2 arerepeated.

A final follow-up visit is conducted one week after the last dose oftest article in Treatment Period 2.

Example 17 Pharmaceutical Compositions Example 17a ParenteralComposition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) is dissolved in DMSO and then mixed with 10 mL of 0.9%sterile saline. The mixture is incorporated into a dosage unit formsuitable for administration by injection.

Example 17b Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) is mixed with 750 mg of starch. The mixture is incorporatedinto an oral dosage unit for, such as a hard gelatin capsule, which issuitable for oral administration.

Example 17c Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) with 420 mg of powdered sugarmixed, with 1.6 mL of light corn syrup, 2.4 mL distilled water, and 0.42mL mint extract. The mixture is gently blended and poured into a mold toform a lozenge suitable for buccal administration.

Example 17d Fast-Disintegrating Sublingual Tablet

A fast-disintegrating sublingual tablet is prepared by mixing 48.5% byweigh of a compound of Formula (I), Formula (II), Formula (III), Formula(IV) or Formula (V), 44.5% by weight of microcrystalline cellulose(KG-802), 5% by weight of low-substituted hydroxypropyl cellulose (50μm), and 2% by weight of magnesium stearate. Tablets are prepared bydirect compression (AAPS PharmSciTech. 2006; 7(2):E41). The total weightof the compressed tablets is maintained at 150 mg. The formulation isprepared by mixing the amount of compound of Formula (I), Formula (II),Formula (III), Formula (IV) or Formula (V) with the total quantity ofmicrocrystalline cellulose (MCC) and two-thirds of the quantity oflow-substituted hydroxypropyl cellulose (L-HPC) by using a threedimensional manual mixer (Inversina®, Bioengineering AG, Switzerland)for 4.5 minutes. All of the magnesium stearate (MS) and the remainingone-third of the quantity of L-HPC are added 30 seconds before the endof mixing.

Example 17e Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of Formula (I), Formula (II), Formula (III), Formula (IV)or Formula (V) is mixed with 50 mg of anhydrous citric acid and 100 mLof 0.9% sodium chloride solution. The mixture is incorporated into aninhalation delivery unit, such as a nebulizer, which is suitable forinhalation administration.

Example 17f Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) is mixed with 2.5 g of methylcelluose (1500 mPa), 100 mg ofmethylparapen, 5 g of glycerin and 100 mL of purified water. Theresulting gel mixture is then incorporated into rectal delivery units,such as syringes, which are suitable for rectal administration.

Example 17g Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) is mixed with 1.75 g of hydroxypropyl celluose, 10 mL ofpropylene glycol, 10 mL of isopropyl myristate and 100 mL of purifiedalcohol USP. The resulting gel mixture is then incorporated intocontainers, such as tubes, which are suitable for topicaladministration.

Example 17h Ophthalmic Solution Composition

To prepare a pharmaceutical opthalmic solution composition, 100 mg of acompound of Formula (I), Formula (II), Formula (III), Formula (IV) orFormula (V) is mixed with 0.9 g of NaCl in 100 mL of purified water andfiltered using a 0.2 micron filter. The resulting isotonic solution isthen incorporated into ophthalmic delivery units, such as eye dropcontainers, which are suitable for ophthalmic administration.

Example 17i Nasal Spray Solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compound ofFormula (I), Formula (II), Formula (III), Formula (IV) or Formula (V) ismixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). Thesolution is placed in a nasal administrator designed to deliver 100 μlof spray for each application.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

1. A compound having the structure of Formula (I), pharmaceuticallyacceptable salt, or N-oxide thereof:

wherein, ring B is a substituted or unsubstituted heteroaryl, wherein ifring B is substituted, then each substituent on ring B is independentlyselected from H and R^(B); X is a bond, —O—, —S—, —S(═O)—, —S(═O)₂—,—NR¹³—, —CH₂—, or —C(═O)—; Q is —C(═O)-Q¹, tertrazolyl, or a carboxylicacid bioisostere; Q¹ is —OH, —OR¹⁵, —NHSO₂R⁹, —N(R¹⁰)₂, —NH—OH, or—NH—CN; each R¹ is independently selected from H, F, —CH₃ and —CH₂CH₃;each of R², R³, R⁴, R⁵ and R^(B) is independently selected from H,halogen, —CN, —NO₂, —OH, —OR¹⁰, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹,—N(R¹⁰)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —C(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰,—N(R¹⁰)₂, —NHCH₂CO₂R¹⁰, —OCH₂CO₂R¹⁰, —SCH₂CO₂R¹⁰, —C(═O)N(R¹⁰)₂,—OC(═O)N(R¹⁰)₂, —NR¹⁰C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹,—NR¹⁰—C₁-C₄alkyl-C(═O)R⁹, —NR¹⁰C(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; each R⁶ is H; R⁷ is —C(═O)R¹¹,—C(═O)OR¹², —C(═O)N(R¹³)₂, —S(═O)₂N(R¹³)₂ or —S(═O)₂R¹²; R¹¹ isC₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted orunsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, asubstituted or unsubstituted heteroaryl, —C₁-C₄alkyl-(substituted orunsubstituted C₃-C₁₀cycloalkyl), —C₁-C₄alkyl-(substituted orunsubstituted C₂-C₁₀heterocycloalkyl), —C₁-C₄alkyl-(substituted orunsubstituted aryl) or —C₁-C₄alkyl-(substituted or unsubstitutedheteroaryl); or R¹¹ is L³-X³-Q³; L³ is a C₁-C₆alkylene; X³ is a bond,—O—, —S—, —S(═O)—, —S(═O)₂—, or —NR¹³—; Q³ is a C₁-C₆alkyl,C₁-C₆fluoroalkyl a substituted or unsubstituted C₃-C₁₀cycloalkyl, asubstituted or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted orunsubstituted aryl, a substituted or unsubstituted heteroaryl,—C₁-C₄alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₄alkyl-(substituted or unsubstituted heterocycloalkyl),—C₁-C₄alkyl-(substituted or unsubstituted aryl), orC₁-C₄alkyl-(substituted or unsubstituted heteroaryl); R¹² is C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or unsubstitutedC₃-C₁₀cycloalkyl, a substituted or unsubstituted C₂-C₁₀heterocycloalkyl,a substituted or unsubstituted aryl, a substituted or unsubstitutedheteroaryl, —C₁-C₄alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₄alkyl-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl),—C₁-C₄alkyl-(substituted or unsubstituted aryl) or—C₁-C₄alkyl-(substituted or unsubstituted heteroaryl); each R¹³ isindependently H, —CN, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, asubstituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted orunsubstituted C₂-C₁₀heterocycloalkyl, a substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —C₁-C₄alkyl-(substitutedor unsubstituted C₃-C₁₀cycloalkyl), —C₁-C₄alkyl-(substituted orunsubstituted C₂-C₁₀heterocycloalkyl), —C₁-C₄alkyl-(substituted orunsubstituted aryl) or —C₁-C₄alkyl-(substituted or unsubstitutedheteroaryl); or two R¹³ groups attached to the same N atom are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted heterocycle; R⁸ is C₁-C₆alkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, (a substituted or unsubstitutedmonocyclic or bicyclic C₃-C₁₀cycloalkyl), (a substituted orunsubstituted monocyclic or bicyclic C₃-C₁₀heterocycloalkyl), asubstituted or unsubstituted aryl, or a substituted or unsubstitutedheteroaryl, C₁-C₄alkylene-R¹⁴, —C₁-C₄alkylene-O—R¹⁴,—C₁-C₄alkylene-S—R¹⁴, —C₁-C₄alkylene-S(═O)₂—R¹⁴, —C₁-C₄alkylene-N(R¹⁴)₂,—C₁-C₄alkylene-C(═O)—R¹⁴, —C₁-C₄alkylene-C(═O)O—R¹⁴—,—C₁-C₄alkylene-OC(═O)—R¹⁴, —C₁-C₄alkylene-NR¹⁴C(═O)—R¹⁴ or—C₁-C₄alkylene-C(═O)N(R¹⁴)₂; each R¹⁴ is independently selected from H,C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, a substituted orunsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, asubstituted or unsubstituted benzyl, or a substituted or unsubstitutedheteroaryl; R⁹ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, asubstituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted orunsubstituted C₂-C₁₀heterocycloalkyl, a substituted or unsubstitutedaryl, a substituted or unsubstituted benzyl, a substituted orunsubstituted heteroaryl, —C₁-C₄alkyl-(substituted or unsubstitutedC₃-C₁₀cycloalkyl), —C₁-C₄alkyl-(substituted or unsubstitutedC₂-C₁₀heterocycloalkyl), —C₁-C₄alkyl-(substituted or unsubstitutedaryl), or —C₁-C₄alkyl-(substituted or unsubstituted heteroaryl); eachR¹⁰ is independently selected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆fluoroalkyl, a substituted or unsubstituted C₃-C₁₀cycloalkyl, asubstituted or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted orunsubstituted aryl, a substituted or unsubstituted benzyl, a substitutedor unsubstituted heteroaryl, —C₁-C₄alkyl-(substituted or unsubstitutedC₃-C₁₀cycloalkyl), —C₁-C₄alkyl-(substituted or unsubstitutedC₂-C₁₀heterocycloalkyl), —C₁-C₄alkyl-(substituted or unsubstitutedaryl), and —C₁-C₄alkyl-(substituted or unsubstituted heteroaryl); or twoR¹⁰ groups attached to the same N atom are taken together with the Natom to which they are attached to form a substituted or unsubstitutedheterocycloalkyl; and each R¹⁵ is independently selected from H andC₁-C₆alkyl.
 2. The compound of claim 1, or a pharmaceutically acceptablesalt, or N-oxide thereof, wherein: X is a bond, —O—, or —CH₂—.
 3. Thecompound of claim 2, or a pharmaceutically acceptable salt, or N-oxidethereof, wherein: X is a bond.
 4. The compound of claim 3, or apharmaceutically acceptable salt, or N-oxide thereof, wherein: ring B isa substituted or unsubstituted monocyclic heteroaryl ring or asubstituted or unsubstituted bicyclic heteroaryl ring, where ring Bcontains 0-1 oxygen atoms; 0-1 sulfur atoms; and 0-4 nitrogen atoms,wherein if ring B is substituted, then each substituent on ring B isindependently selected from H and R^(B).
 5. The compound of claim 4, ora pharmaceutically acceptable salt, or N-oxide thereof, wherein: ring Bis a substituted or unsubstituted heteroaryl ring selected frompyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thienyl,furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl,pyrazolyl, isothiazolyl, triazolyl, tetrazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl,indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, azaindolyl,pyrazolopyridinyl, thiazolopyrimidinyl, thiazolopyridinyl,pyridothienyl, pyrimidiothienyl and pyrrolopyrimidinyl, wherein if ringB is substituted, then each substituent on ring B is independentlyselected from H and R^(B).
 6. (canceled)
 7. (canceled)
 8. (canceled) 9.The compound of claim 5, or a pharmaceutically acceptable salt, orN-oxide thereof, wherein: ring B is a substituted or unsubstituted6-membered monocyclic heteroaryl ring, where ring B contains 1 or 2nitrogen atoms, wherein if ring B is substituted, then each substituenton ring B is independently selected from H and R^(B).
 10. (canceled) 11.(canceled)
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 14. The compound of claim 4, ora pharmaceutically acceptable salt, or N-oxide thereof, wherein: ring Bis a substituted or unsubstituted bicyclic heteroaryl ring, where ring Bcontains 0-1 oxygen atoms; 0-1 sulfur atoms; and 1-4 nitrogen atoms,wherein if ring B is substituted, then each substituent on ring B isindependently selected from H and R^(B).
 15. (canceled)
 16. The compoundof claim 4, or a pharmaceutically acceptable salt, or N-oxide thereof,wherein: the groups

 are on adjacent atoms of ring B.
 17. (canceled)
 18. The compound ofclaim 16, or a pharmaceutically acceptable salt, or N-oxide thereof,wherein: Q is —C(═O)-Q¹; Q¹ is —OH or —OR¹⁵; each R¹ is independentlyselected from H, F, and —CH₃; R⁷ is —C(═O)R¹¹, —C(═O)OR¹², or—C(═O)N(R¹³)₂; R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, (asubstituted or unsubstituted monocyclic or bicyclic C₃-C₁₀cycloalkyl),(a substituted or unsubstituted monocyclic or bicyclicC₂-C₁₀heterocycloalkyl), a substituted or unsubstituted aryl, or asubstituted or unsubstituted heteroaryl, C₁-C₆alkylene-R¹⁴,—C₁-C₆alkylene-O—R¹⁴, —C₁-C₆alkylene-NR¹⁰—R¹⁴, —C₁-C₆alkylene-C(═O)—R¹⁴,—C₁-C₆alkylene-C(═O)O—R¹⁴—, or —C₁-C₆alkylene-C(═O)NR¹⁰—R¹⁴; each R¹⁴ isindependently selected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, a substituted or unsubstituted cycloalkyl, a substitutedor unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl,a substituted or unsubstituted benzyl, or a substituted or unsubstitutedheteroaryl.
 19. (canceled)
 20. The compound of claim 18, or apharmaceutically acceptable salt, or N-oxide thereof, wherein: Q¹ is—OH; each R¹ is H; each of R², R³, and R⁴ is each independently H,halogen, —CN, —OH, —OR¹⁰, C₁-C₄alkyl, C₁-C₄fluoroalkyl,C₁-C₄fluoroalkoxy, C₁-C₄alkoxy, or C₁-C₄heteroalkyl; R⁵ is H.
 21. Thecompound of claim 20, or a pharmaceutically acceptable salt, or N-oxidethereof, wherein: R¹¹ is C₁-C₄alkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, a substituted or unsubstituted monocyclicheteroaryl, —C₁-C₂alkyl-(substituted or unsubstituted phenyl) or—C₁-C₂alkyl-(substituted or unsubstituted monocyclic heteroaryl); or R¹¹is L³-X³-Q³; L³ is a C₁-C₄alkylene; X³ is a bond, or —O—; Q³ is aC₁-C₆alkyl, substituted or unsubstituted phenyl, or—C₁-C₄alkyl-(substituted or unsubstituted phenyl); R¹² is C₁-C₆alkyl,C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, a substituted orunsubstituted monocyclic heteroaryl, —C₁-C₂alkyl-(substituted orunsubstituted phenyl) or —C₁-C₂alkyl-(substituted or unsubstitutedmonocyclic heteroaryl); each R¹³ is independently H, C₁-C₆alkyl,C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, substituted orunsubstituted monocyclic heteroaryl, —C₁-C₂alkyl-(substituted orunsubstituted phenyl) or —C₁-C₂alkyl-(substituted or unsubstitutedmonocyclicheteroaryl).
 22. (canceled)
 23. The compound of claim 21, or apharmaceutically acceptable salt, or N-oxide thereof, wherein: R⁸ isC₁-C₆alkyl, C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, or asubstituted or unsubstituted monocyclic heteroaryl, or—C₁-C₄alkylene-R¹⁴; R¹⁴ is C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, or a substituted or unsubstituted monocyclicheteroaryl.
 24. The compound of claim 23, or a pharmaceuticallyacceptable salt, or N-oxide thereof, wherein: R¹¹ is C₁-C₄alkyl,C₃-C₆cycloalkyl, —C₁-C₂alkyl-(substituted or unsubstituted phenyl) or—C₁-C₂alkyl-(substituted or unsubstituted monocyclic heteroaryl); or R¹¹is L³-X³-Q³; L³ is a C₁-C₄alkylene; X³ is a bond, or —O—; Q³ is aC₁-C₆alkyl, substituted or unsubstituted phenyl, or—C₁-C₄alkyl-(substituted or unsubstituted phenyl); R¹² is C₁-C₆alkyl,—C₁-C₂alkyl-(substituted or unsubstituted phenyl) or—C₁-C₂alkyl-(substituted or unsubstituted monocyclic heteroaryl); eachR¹³ is independently H, C₁-C₆alkyl, —C₁-C₂alkyl-(substituted orunsubstituted phenyl) or —C₁-C₂alkyl-(substituted or unsubstitutedmonocyclicheteroaryl).
 25. The compound of claim 24, or apharmaceutically acceptable salt, or N-oxide thereof, wherein: R⁸ isC₁-C₄alkyl, C₃-C₆cycloalkyl, or —C₁-C₂alkylene-R¹⁴; R¹⁴ isC₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, or a substitutedor unsubstituted monocyclic heteroaryl.
 26. The compound of claim 25, ora pharmaceutically acceptable salt, or N-oxide thereof, wherein: ring Bis a substituted or unsubstituted pyridinyl, wherein if ring B issubstituted, then ring B is substituted with 1 or 2 R^(B).
 27. Thecompound of claim 26, or a pharmaceutically acceptable salt, or N-oxidethereof, wherein: each R^(B) is independently selected from H, halogen,—CN, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, C₁-C₄alkoxy,and C₁-C₄heteroalkyl.
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 32. The compound of claim 25, or a pharmaceuticallyacceptable salt, or N-oxide thereof, wherein: ring B is a substituted orunsubstituted quinolinyl, wherein if ring B is substituted, then ring Bis substituted with 1 or 2 R^(B); each R^(B) is independently selectedfrom H, halogen, —CN, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl,C₁-C₄fluoroalkoxy, C₁-C₄alkoxy, and C₁-C₄heteroalkyl.
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 91. A compound that is:{3-[3-(Benzyloxycarbonylamino-methyl)-pyridin-2-yl]-4-methoxy-phenyl}-aceticacid (Compound 1-1);(3-{3-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-5-methyl-pyridin-2-yl}-4-methoxy-phenyl)-aceticacid (Compound 1-2);[3-(3-{[Ethyl-(3-phenyl-propionyl)-amino]-methyl}-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-aceticacid (Compound 1-3);{3-[3-(3-Benzyl-1-ethyl-ureidomethyl)-5-methyl-pyridin-2-yl]-4-methoxy-phenyl}-aceticacid (Compound 1-4);(3-{2-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-pyridin-3-yl}-4-methoxy-phenyl)-aceticacid (Compound 1-5);{3-[2-(3-Benzyl-1-ethyl-ureidomethyl)-6-methoxy-pyridin-3-yl]-4-methoxy-phenyl}-aceticacid (Compound 1-6);(3-{2-[(Acetyl-ethyl-amino)-methyl]-6-methoxy-pyridin-3-yl}-4-methoxy-phenyl)-aceticacid (Compound 1-7);(3-{3-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-aceticacid (Compound 2-1);(3-{3-[(Acetyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-aceticacid (Compound 2-2);[3-(3-{[Ethyl-(2-methoxy-acetyl)-amino]-methyl}-quinolin-2-yl)-4-methoxy-phenyl]-aceticacid (Compound 2-3);(3-{2-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid (Compound 2-4);(3-{2-[(Ethyl-propionyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid (Compound 2-5);3-(2-{[Ethyl-(2-methoxy-acetyl)-amino]-methyl}-quinolin-3-yl)-4-methoxy-phenyl]-aceticacid (Compound 2-6);(3-{2-[(Acetyl-benzyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid (Compound 2-7); or(3-{2-[(Benzyl-cyclopropanecarbonyl-amino)-methyl]-quinolin-3-yl}-4-methoxy-phenyl)-aceticacid (Compound 2-8); or a pharmaceutically acceptable salt, or N-oxidethereof.
 92. (canceled)
 93. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable inactive ingredient selected frompharmaceutically acceptable diluents, pharmaceutically acceptableexcipients, and pharmaceutically acceptable carriers.
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 99. (canceled)100. A method for treating asthma, rhinitis, allergic conjuctivitis,atopic dermatitis, chronic obstructive pulmonary disease (COPD),pulmonary hypertension, interstitial lung fibrosis, arthritis, allergy,psoriasis, inflammatory bowel disease, adult respiratory distresssyndrome, myocardial infarction, aneurysm, stroke, cancer, woundhealing, endotoxic shock, pain, inflammatory conditions, eosinophilicesophagitis, eosinophil-associated gastrointestinal disorders (EGID),idiopathic hypereosinophilic syndrome, otitis, airway constriction,mucus secretion, nasal congestion, increased microvascular permeabilityand recruitment of eosinophils, urticaria, sinusitis, angioedema,anaphylaxia, chronic cough or Churg Strauss syndrome in a mammalcomprising administering to the mammal a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable salt,or N-oxide thereof.
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